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TW200840567A - Novel oxadiazole compounds - Google Patents

Novel oxadiazole compounds Download PDF

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Publication number
TW200840567A
TW200840567A TW096148339A TW96148339A TW200840567A TW 200840567 A TW200840567 A TW 200840567A TW 096148339 A TW096148339 A TW 096148339A TW 96148339 A TW96148339 A TW 96148339A TW 200840567 A TW200840567 A TW 200840567A
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TW
Taiwan
Prior art keywords
optionally substituted
phenyl
alkyl
group
compound
Prior art date
Application number
TW096148339A
Other languages
Chinese (zh)
Inventor
Adrian D Hobson
Shannon R Fix-Stenzel
Kevin P Cusack
Eric C Breinlinger
Graham K Ansell
Robert H Stoffel
Kevin R Woller
Pintipa Grongsaard
Original Assignee
Abbott Lab
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Publication of TW200840567A publication Critical patent/TW200840567A/en

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    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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Abstract

Novel ox diazole compounds, pharmaceutical compositions containing such compounds and the use of those compounds or compositions as agonists or antagonists of the S1P family of G protein-coupled receptors for treating diseases associated with modulation of S1P family receptor activity, in particular by affording a beneficial immunosuppressive effect are disclosed.

Description

200840567 九、發明說明： 【發明所屬之技術領域】 • 相關申請案之交叉參考 • 本申請案主張2006年12月21曰申請之美國臨時申請案編 號第60/875,251號之優先權。 本發明揭示新穎崎二唑化合物、含此等化合物之醫藥組 合物及此等化合物或組合物作為S1P族之G蛋白質-偶合受 體的激動劑或拮抗劑以治療與S1P族受體活性之調控有關 # 疾病，尤其是藉由提供有利之免疫壓抑效果之用途。 【先前技術】 神經鞘氨醇（Sphing0Sine)_卜磷酸酯（S1P)為神經鞘磷酯 (sphingomyelin)生物合成路徑之一部份且已知會影響多重 生物過程。S1P係經由鞘氨醇激酶（SK1及SK2)對鞘氨醇磷 酸化而形成且藉鞘氨醇裂解酶的斷裂而降解而形成棕櫚醛 及磷醯乙醇胺或經由磷脂質磷酸酶的去磷醯化而降解。其 在血清中以高含量存在（約5〇〇 ηΜ)且見於大部份組織中。 • 其可於廣泛種類細胞中反應於數種刺激而合成，其包含細 胞素、生長因子及G蛋白質·偶合之受體（GPCR)配位體。 可結合S1P(目前已知為sip受體S1P1-5)之GRCRs經由百曰 咳毒素敏感性（Gi)路徑以及百日咳毒素不敏感路徑偶合而 刺激各種過程。該S1P族之個別受體同時為組織及反應特 異者且因此作為治療標輕倍感興趣。 s 1P自細胞及組織引出許多反應。尤其，s 1P已顯示為對 所有五種 GPCRs、SlPl(Edg-l)、SlP2(Edg-5)、SlP3(Edg- 127788.doc 200840567 3)、SlP4(Edg-6)及Slp5(Edg_8)之激動齊卜sip在該⑽受 體上之作用6連結至對細胞社之抗性、細胞型態的改 义、田胞遷移、生長、分化、細胞分裂、血管新生及經由 淋巴細胞運輸改變而調節免疫系统。因此，sip受體為治 療Ή如％瘤疾病、自體免疫疾病及移植中組織排斥之標 靶該等又體亦與結構相關之溶胞碟碟脂酸（LpA)之三種 溶胞填脂質受體LPAl、LPAmLPA3共有5〇_55%之胺基酸 相同性。。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The present invention discloses novel soxadiazole compounds, pharmaceutical compositions containing the same, and conjugates or antagonists of such compounds or compositions as S1P G protein-coupled receptors for the treatment of S1P receptor activity About #病, especially by providing a beneficial immunosuppressive effect. [Prior Art] Sphingosine (S1P) is part of the biosynthesis pathway of sphingomyelin and is known to affect multiple biological processes. S1P is formed by phosphorylation of sphingosine via sphingosine kinase (SK1 and SK2) and degraded by sphingosine cleavage to form palmalin and phosphonium ethanolamine or dephosphorization via phospholipid phosphatase And degradation. It is present in high levels in serum (about 5 〇〇 η Μ) and is found in most tissues. • It can be synthesized in a wide variety of cells in response to several stimuli, including cytokines, growth factors, and G protein/coupled receptor (GPCR) ligands. GRCRs that bind to S1P (currently known as sip receptor S1P1-5) stimulate the various processes via the cough sputum sensitivity (Gi) pathway and pertussis toxin insensitive pathway coupling. The individual receptors of the S1P family are both tissue and response specific and therefore are of light interest as therapeutic targets. s 1P elicits many reactions from cells and tissues. In particular, s 1P has been shown to be used for all five GPCRs, SlPl (Edg-1), SlP2 (Edg-5), SlP3 (Edg-127788.doc 200840567 3), SlP4 (Edg-6), and Slp5 (Edg_8). The role of agitated sip at the (10) receptor is linked to cell resistance, cell type remodeling, cell migration, growth, differentiation, cell division, angiogenesis, and regulation via lymphocyte trafficking. immune system. Therefore, the sip receptor is a target for the treatment of tissue diseases such as % tumor disease, autoimmune disease, and tissue rejection in transplantation. These three lytic lipid-filled lipids of structure-associated lysate discoic acid (LpA) are also involved. The body LPAl, LPAmLPA3 has a total of 5 〇 55% amino acid identity.

GPCRs為優異的藥物標乾，在多重疾病領域有數種上市 藥例子。GPCRs為可結合細胞的細胞外表面上激素且可將 訊號傳導通過細胞膜至細胞内部之細胞表面受體。該内部 訊號經由與G蛋白質相互作用而擴心隨後與各種第二信 使路徑相互作用。此傳導路徑顯示於下游細胞反應中，其 包含細胞骨架改變、細胞運動性、增生、細胞凋亡、蛋白 質表現之分泌及調節等。S1P受體由於個別受體於不同組 織中表現而為良好藥物標靶且訊號通過不同路徑使該個別 受體同時具有組織及反應特異性。S1P受體之組織特異性 由於對於-種受體發展出激動劑或拮&劑之選擇性而使細 胞對含該受體之組織的反應局部化，限制了非所欲副作用 而為所需。該S1P受體之反應特異性由於使其可發展可起 始或壓抑某種細胞反應而不影響其他反應之激動劑或拮抗 劑而亦具有重要性。例如，該Slp受體之反應特異性可使 得S1P擬物（mimetic)可起始血小板凝集作用而不影響細胞 形態學。 127788.doc 200840567 刺激個別S 1P受體之生理學牽連由於部份缺乏受體類型 選擇性配位體而大多為未知。具有Slp受體之強效激動劑 或拮抗劑活性之S 1P類似物之分離及特性化受到限制。GPCRs are excellent drug standards and there are several examples of marketed drugs in multiple disease areas. GPCRs are cell surface receptors that bind to hormones on the extracellular surface of cells and conduct signals through the cell membrane to the interior of the cell. The internal signal is expanded by interaction with the G protein and then interacts with various second messenger paths. This conduction pathway is shown in downstream cellular responses, including cytoskeletal changes, cell motility, proliferation, apoptosis, secretion and regulation of protein expression. The S1P receptor is a good drug target due to the expression of individual receptors in different tissues and the signal has different tissue and reaction specificities through different routes. The tissue specificity of the S1P receptor localizes the response of the cell to the tissue containing the receptor due to the development of an agonist or antagonist's selectivity, limiting the unwanted side effects . The specificity of the reaction of the S1P receptor is also important because it allows the development of agonists or antagonists that can initiate or suppress certain cellular responses without affecting other responses. For example, the specificity of the reaction of the Slp receptor allows the S1P mimetic to initiate platelet aggregation without affecting cell morphology. 127788.doc 200840567 Stimulation of the physiological involvement of individual S 1P receptors is largely unknown due to the partial lack of receptor type selective ligands. The isolation and characterization of S 1P analogs with potent agonist or antagonist activity of the Slp receptor is limited.

例如S1P為廣泛表現且由於大血管破裂故敲除基因鼠引 起胚胎致死率。使用得自s 1P1敲除基因鼠之淋巴細胞的繼 代（adoptive)細胞轉移實驗已顯示S1P1缺乏淋巴細胞引退 至次要淋巴器官。相反地，τ細胞過度表現slpHf先區隔 成該血液劃區（compartment)而非次要淋巴器官。該等實驗 提供該S 1P1為與淋巴歸向（h〇ming)及運輸至次 要淋巴劃區的證明。 目前，需要-種為該S1P受體族之個別受體的激動劑或 拮抗劑之新穎、強效及選擇性藥劑以解決與該S1P受體族 之個別受體的激動機制或拮抗機制有關之不適合醫藥需 求0 【發明内容】 本發明提供一種以请+ m 、 通式⑴、（Ia)、（Π)、（III)、（IV)、 (IVa)及（IVb)所描述之作為Γ 作為G蛋白質-偶合之受體S1P1之新 穎化合物。此等介人仏 、°物可減”-及B-淋巴細胞循環及滲透 數獲仔有利之免将懕女冬 亦展現活性。_^°”化合物㈣P受體族内 本發明之第一具體例係提供For example, S1P is widely manifested and knockout genetic mice cause embryonic lethality due to rupture of large blood vessels. The use of alternative cell transfer experiments using lymphocytes derived from s 1P1 knockout gene mice has shown that S1P1 lacks lymphocytes to retreat to secondary lymphoid organs. Conversely, tau cells overexpress slpHf to first divide the blood into compartments rather than secondary lymphoid organs. These experiments provide evidence that the S 1P1 is associated with lymphatics and transported to secondary lymph nodes. At present, there is a need for novel, potent and selective agents that are agonists or antagonists of individual receptors of the S1P receptor family to address the agonistic or antagonistic mechanisms of individual receptors of the S1P receptor family. Unsuitable for medical needs 0 [Description of the Invention] The present invention provides a method for treating + m , general formula (1), (Ia), (Π), (III), (IV), (IVa) and (IVb) as A novel compound of the G protein-coupled receptor S1P1. These mediators, ° substances can be reduced"- and B-lymphocyte circulation and the number of penetrations are beneficial to the prostitutes to show activity in the winter. _^ °" compound (four) P receptor family within the first specific of the invention Case

種下式I之化合物 / R1Compound of formula I / R1

式I 127788.doc 200840567 -西藥可接叉性鹽、生物上活性代謝物、溶劑化物、水合 物則藥、對映異構物或立體異構物，其中 L為一鍵或視情況取代烷基； 主 R 為-c(o)_nh-苯基、-NH_c(〇)^* 喃基…;^11_8(〇)2_視 U况取代之苯基、-〇-視情況取代之（q-co烷基、-s-視情 况取代之（Ci-C3)烷基、視情況取代之（C2-C6)烷基、視情況 取代之胺基、視情況取代i(C3_C6)環烷基、-(CH2)(C3)烷 基、四氫苯并呋喃基、呋喃基、四氫呋喃基、視情況取代 鲁 5 一虱異,°朵基、視情況取代之味唆基、視情況取代 之5丨°木基、視情況取代之異呤唑基、視情況取代之嗎啉 基視h況取代之萘基、視情況取代之苯基、_〇_CH2•苯 基、苯基、_0-視情況取代之苯基、視情況取代之哌啶 基、視情況取代之吡唑基、視情況取代之吡啶基、視情況 取代之嘧啶基、視情況取代之咄咯啶基、視情況取代之 1，2,3,4-四氫異喹啉基、視情況取代之喹啉基、視情況取 代之5,6,7,8-四氫咪唑并[i，2_a]吡嗪基、視情況取代之吡咯 籲&、視情況取代之啥琳基、視情況取代之嚷嗤基或視情泥 取代之噻吩基； R2為 Br、ci、CF3、CN或-CKCrCJ烷基； r3為視情況取代之-(C3-C8)烷基、((VC5)烯基、(κ5) 快基、視情況取代之-(C^C6)環烷基、-烷基七_視 情況取代之（Cl_C3)烷基、-(C1-C3)烷基-咪唑基、_(Ci_C3) 烧基-嗎啉基、-(C1-C3)烷基-視情況取代之笨基、 烧基-視情況取代之哌嗪基、_(Ci-C3)烷基-吡洛咬基、 127788.doc -9- 200840567 _(C1-C3)烧基-嗟吩基、四氫呋喃基 ’（C1-C3)燒基-α辰π定基、 或嘆嗤基；且 R6 為 Η ; 但限制條件為 R1不經視情況取代之 〜之衣己基、-c(o)_環己基或_ΝΗ·環己 基取代； 二^ c3)烧基日夺，為視情況取代之異口号哇基； 曰R為視丨月況取代之(Cl)烷基時，L-R1不為環己基或 -CH2-環己基；且 限制條件為該化合物不為下列化合物 CH, 本發明之第二具體例係提供一種具體例1之化合物，其 中R1係視情況經一或多個選自下列之取代基取代：Br、 C卜F、CF3、CN、側氧基、視情況取代之（Ci_c6)烷基、 泰 視^況取代之（C^C6)烯基、視情況取代之胺基 、視情況取 代之（eve：6)環烧基、_CH广視情況取代之旅咬基、_c(〇)、 視情況取代之（Cpco烷基、-C(0)_nr-(Ci_C6)烷基、 -C(0)-0-視情況取代之（Ci_c6)烷基、·〇_視情況取代之（C1_ c6)烧基…NH_(C3_C6)環烷基、-NH-CCCO-CKCVCO 烷 基、-S(0)2-N(R9)2、_s(〇)2_NH-視情況取代之（Ci_c4)烷 基、-NH-視情況取代之（Ci_c6)烧基…NH-C(〇)-tJ夫喃基、 -NH-S(O)2-視情況取代之苯基、視情況取代之吡啶基、 127788.doc -10- 200840567 〇、 to 、\。Formula I 127788.doc 200840567 - Western medicine cleavable salts, biologically active metabolites, solvates, hydrates, enantiomers or stereoisomers wherein L is a bond or optionally substituted alkyl The main R is -c(o)_nh-phenyl, -NH_c(〇)^* 基基...;^11_8(〇)2_Substituting phenyl, -〇- as the case of U: Coalkyl, -s- optionally substituted (Ci-C3)alkyl, optionally substituted (C2-C6)alkyl, optionally substituted amine, optionally substituted i(C3_C6)cycloalkyl, - (CH2) (C3) alkyl, tetrahydrobenzofuranyl, furyl, tetrahydrofuranyl, as appropriate, substituted for Lu 5, a strange, base, as appropriate, substituted for the sulfhydryl group, as appropriate, 5 丨 ° Wood-based, optionally substituted isoxazolyl, optionally substituted morpholinyl substituted naphthyl, optionally substituted phenyl, _〇_CH2•phenyl, phenyl, _0- optionally substituted Phenyl, optionally substituted piperidinyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyridyl, optionally substituted 1,2 , 3, 4-four Hydroisoisoquinolyl, optionally substituted quinolinyl, optionally substituted 5,6,7,8-tetrahydroimidazo[i,2_a]pyrazinyl, optionally substituted pyrrole & Substituted thiophene, optionally substituted thiol or thiophene substituted by the mud; R2 is Br, ci, CF3, CN or -CKCrCJ alkyl; r3 is optionally substituted with -(C3-C8) alkane Base, ((VC5) alkenyl, (κ5) fast radical, optionally substituted -(C^C6)cycloalkyl, -alkyl-7, optionally substituted (Cl_C3)alkyl, -(C1-C3) Alkyl-imidazolyl, _(Ci_C3)alkyl-morpholinyl, -(C1-C3)alkyl--substituted, optionally substituted, piperazine-substituted piperazinyl, _(Ci-C3) Alkyl-pyrrolidine, 127788.doc -9- 200840567 _(C1-C3)alkyl-brenyl, tetrahydrofuranyl '(C1-C3)alkyl-α π 定, or sulphonyl; R6 is Η; but the restriction condition is that R1 is replaced by hexyl group, -c(o)-cyclohexyl or _ΝΗ·cyclohexyl group, which is not replaced by the case; and 2^3) is replaced by the case. a different singular number; when 曰R is a (Cl) alkyl group substituted by a month, L-R1 is not a cyclohexyl group or a -CH2-cyclohexyl group; The compound is not the following compound CH, and the second embodiment of the present invention provides a compound of the specific example 1, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of Br, C, and F. , CF3, CN, pendant oxy, optionally substituted (Ci_c6)alkyl, substituted (C^C6)alkenyl, optionally substituted amine, optionally substituted (eve:6) ring Burning base, _CH wide-view situation replaces the bite base, _c (〇), as appropriate (Cpco alkyl, -C(0)_nr-(Ci_C6) alkyl, -C(0)-0- as appropriate Substituted (Ci_c6)alkyl, ·〇_, as appropriate (C1_c6) alkyl (NH_(C3_C6) cycloalkyl, -NH-CCCO-CKCVCO alkyl, -S(0)2-N(R9) 2, _s(〇)2_NH- (Ci_c4) alkyl as appropriate, -NH- optionally substituted (Ci_c6) alkyl...NH-C(〇)-tJ, and -NH-S(O) 2-Substituted phenyl, optionally substituted pyridyl, 127788.doc -10- 200840567 〇, to, \.

OHOH

HNHN

HOHO

HOHO

其中各R9係獨立選自H或視情況取代之（Ci_C6)烧基。 本發明之第三具體例係提供前迷任一具體例之化合物 其中該化合物為式la之化合物：Wherein each R9 is independently selected from H or optionally substituted (Ci_C6) alkyl. A third embodiment of the present invention provides a compound of any of the foregoing specific examples, wherein the compound is a compound of the formula la:

式la 其中L為一鍵。Where la is a bond.

λ第四具體例係提供前述任一具體例之化合物， 其中Rl為視情況取代之苯基或視情況取代之+朵基。 本發明之第五且髀彳^ -體例係心供前述任一具體例之化合物， 其中該化合物為 127788.doc -11 - 200840567The fourth specific example of λ provides a compound of any of the foregoing specific examples, wherein R1 is optionally substituted phenyl or optionally substituted with a phenyl group. The fifth aspect of the present invention is to provide a compound according to any of the foregoing specific examples, wherein the compound is 127788.doc -11 - 200840567

其中y為1或2。Where y is 1 or 2.

本發明第六具體例係提供前述任一 $體例t化合物， 其中 L為視情況取代之烷基； R1為-C⑼-NH·苯基、抓c⑼“夫喃基魯啊”視 情況取代之苯基、視情況取代之_〇餐C3m基、_s_(c C糾、节基氧基、視情況取代之(Μ)環炫基、視情 況取代之㈣基、嗎料、視情況取代之萘基、 代之苯基、視情況取狀苯氧基、視情況取代之 取 視情況取代之哌啶基、視情況取代之吡 ’、土、 之吼㈣基或視情況取代之„塞吩基；Α、視情況取代 R2 為 C1 ; R3為異丙基；且 R6 為 Η。 本發明之第七具體例係提供前述任_ 其中為視情況取代之苯基或視情 127788.doc -12· 200840567 c6)環烷基。 第七具體例之化合物，其 二甲胺基及苯氧基之取代 本發明之第八具體例係提供如 中R1係經一或多個獨立選自F、 基取代。 本發明之第九具體例係提供下式II之化合物：A sixth embodiment of the present invention provides any of the foregoing compounds of the formula t, wherein L is an optionally substituted alkyl group; R1 is -C(9)-NH.phenyl, and c(9) "fuganjilu" is optionally substituted with benzene. Substitute, depending on the situation, _ meal C3m base, _s_ (c C correction, benzyloxy, optionally substituted (Μ) cyclodyl, as appropriate, substituted (four) base, material, optionally substituted naphthyl And substituted phenyl, as the case may be, the phenoxy group, as the case may be substituted, substituted piperidinyl, optionally substituted pyr', earth, ruthenium (tetra) or substituted as appropriate; Α, optionally, R2 is C1; R3 is isopropyl; and R6 is Η. The seventh specific example of the present invention provides the above-mentioned _ which is optionally substituted phenyl or 127788.doc -12· 200840567 C6) A cycloalkyl group. A compound of the seventh embodiment, which is substituted with a dimethylamino group and a phenoxy group. The eighth embodiment of the present invention provides that the R1 group is substituted by one or more independently selected from the group consisting of F and a group. A ninth embodiment of the present invention provides a compound of the following formula II:

式II 其醫藥可接受性鹽、生物上活性代謝物、溶劑化物、水 合物、前藥、對映異構物或立體異構物，其中 Y為一鍵； L為一鍵或ch2 ; R為視情況取代之（c^-c：4)烷基、視情況取代之吲哚基或 視情況取代之苯基； R2為 cf3 ; R3為Η、嗎啉基或（c3-c5)環烷基；且 R為Η 〇 本發明之第十具體例係提供第九具體例之化合物，其中 R1為視情況取代之苯基且R3為嗎啉基。 本發明之第十一具體例係提供具體例九及十之化合物， 其中R1係視情況經一或多個獨立選自下列之取代基取代： C1、視情況取代（CVC3)烷基、 I27788.doc -13- 200840567Formula II is a pharmaceutically acceptable salt, a biologically active metabolite, a solvate, a hydrate, a prodrug, an enantiomer or a stereoisomer wherein Y is a bond; L is a bond or ch2; Substituting (c^-c:4)alkyl, optionally substituted fluorenyl or optionally substituted phenyl; R2 is cf3; R3 is hydrazine, morpholinyl or (c3-c5)cycloalkyl And R is a compound of the ninth embodiment of the present invention, wherein R1 is an optionally substituted phenyl group and R3 is a morpholinyl group. An eleventh embodiment of the present invention provides the compounds of the specific examples 9 and 10, wherein R1 is optionally substituted with one or more substituents independently selected from the group consisting of: C1, optionally substituted (CVC3) alkyl, I27788. Doc -13- 200840567

本發明第十二具體例係提供式ΠΙ之化合物··A twelfth specific example of the present invention provides a compound of the formula

其醫藥可接受性鹽、生物上活性代謝物、溶劑化物、水 合物、前藥、對映異構物或立體異構物，其中 D為CH或Ν ; Υ為一鍵； L為一鍵； R1為視情況取代之苯基； R2 為 Η ; R3為Η ;且 R6為視情況取代之烷基。 本發明第十三具體例係提供第十二具體例之化合物，其 中R1係經C1及異丙氧基取代。 本發明第十四具體例係提供式（IV)之化合物：a pharmaceutically acceptable salt, a biologically active metabolite, a solvate, a hydrate, a prodrug, an enantiomer or a stereoisomer, wherein D is CH or hydrazine; hydrazine is a bond; L is a bond; R1 is a phenyl group optionally substituted; R2 is Η; R3 is Η; and R6 is an optionally substituted alkyl group. A thirteenth embodiment of the present invention provides the compound of the twelfth embodiment, wherein R1 is substituted by C1 and isopropoxy group. A fourteenth embodiment of the invention provides a compound of formula (IV):

或其醫藥可接受性鹽、溶劑化物、水合物、代謝物、前 127788.doc -14- 200840567 藥、對映異構物或立體異構物， 其中： X為N或CR4 ; L為一鍵、-Ch2CH2-、（C3-C6)環烷基或-CHR5 ; Y為-0-、-NR7-或-C(R7)(R7，)-;Or a pharmaceutically acceptable salt, solvate, hydrate, metabolite thereof, 127788.doc -14-200840567 drug, enantiomer or stereoisomer, wherein: X is N or CR4; L is a bond , -Ch2CH2-, (C3-C6)cycloalkyl or -CHR5; Y is -0-, -NR7- or -C(R7)(R7,)-;

Rl為視情況取代之芳基、視情況取代之雜芳基、視情況 取代之雜環基、視情況取代之_(Ci_c6)烷基-〇-((VC3)烷 基、視情況取代之-(CVC6)烧基烧基-〇-(Ci-C3) 烷基、視情況取代之-(CVC6)烷基-ο-芳基、烷基硫基烷 基、未經取代之（C^-C：5)烷基、經取代之（Cl_C6)烷基、 -COR9、視情況取代之 烧基、_n(r7)(r8)、 -n(r7)s〇2-r9或視情況取代之（cvc6)環烷基，且其中Ri不 為經取代之環戊并π塞吩（cyclopentathiophene)、鹵嗟吩、經 取代之二氫茚或經取代之色稀酮； R2及R6可相同或不同且獨立為H、_(Cl-C4)烷基、_〇_ (Ci-CJ烧基、_CF3、CN、i 基或-COCKCi-Cd烧基； R3為視情況取代之芳基、視情況取代之雜環基、視情況 取代之雜芳基、視情況取代之（C3_C6)環烷基、-(CH2)n_R9、 -C0-0R9、_CO-R9、_C〇N(R7)(R9)、-N(R7)(R9)、_S〇R9、_S02R9 及視情況取代之直鏈或分支（Ci_C8)烷基鏈，該烷基鏈視情 況包含嵌在烧基鏈中之、_C〇〇 、_S〇 S〇2 、 -CONH-、-NHCO-、-N-或-Ο-基；且當γ為〇時，R3不為烷 基二氮雜環庚烷、-C(CH3)2COOCH2CH3或-CH2CH2N(CH2CH3)2， 且當Y為-CH2-時，R3不為_CH2C〇〇H ; 127788.doc -15· 200840567 或Y為一鍵且R3為視情況取代之嗎啉基； %、-CN或鹵 R 為H、-(Cl_c4)院基、炫基、 基； 為 H、〇_(CVC3)燒基或（c「C3)炫基； R7或R7’每次出現係獨立為H或視情況取 R8為Η、視情況取代之CH3或-COR9 ;Rl is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted _(Ci_c6)alkyl-fluorene-((VC3)alkyl, as appropriate - (CVC6) alkyl ketone-oxime-(Ci-C3) alkyl, optionally substituted -(CVC6)alkyl-o-aryl, alkylthioalkyl, unsubstituted (C^-C : 5) alkyl, substituted (Cl_C6) alkyl, -COR9, optionally substituted alkyl, _n(r7)(r8), -n(r7)s〇2-r9 or optionally substituted (cvc6 a cycloalkyl group, and wherein Ri is not a substituted cyclopentathiophene, a halophene, a substituted indoline or a substituted diester; R2 and R6 may be the same or different and independent Is H, _(Cl-C4)alkyl, _〇_ (Ci-CJ alkyl, _CF3, CN, i or -COCKCi-Cd alkyl; R3 is an optionally substituted aryl, optionally substituted a cyclic group, optionally substituted heteroaryl, optionally substituted (C3_C6)cycloalkyl, -(CH2)n_R9, -C0-0R9, _CO-R9, _C〇N(R7)(R9), -N( R7)(R9), _S〇R9, _S02R9 and, optionally, a straight or branched (Ci_C8) alkyl chain, which optionally comprises In the alkyl chain, _C〇〇, _S〇S〇2, -CONH-, -NHCO-, -N- or -Ο-yl; and when γ is 〇, R3 is not alkyldiazepine Alkane, -C(CH3)2COOCH2CH3 or -CH2CH2N(CH2CH3)2, and when Y is -CH2-, R3 is not _CH2C〇〇H; 127788.doc -15· 200840567 or Y is a bond and R3 is a visual Substituted morpholinyl; %, -CN or halogen R is H, -(Cl_c4), leuco, base; H, 〇_(CVC3) alkyl or (c "C3) 炫; R7 or Each occurrence of R7' is H independently or, depending on the situation, R8 is Η, CH3 or -COR9, as appropriate;

R9為氫、視情況取代之(C,-C3)烧基、视情況取代之块 視情況取代之芳基、視情況取代之雜芳基、視情況取 代之雜環基或視情況取代之（C3_C6)環烷基；且 η為 1、2、3或 4 ; 但限制條件為 _c(〇l·視情況取代之呋喃 R不為視情況取代之ϋ夫喃基或 基； R不為視情況取代之啥琳基； R9不為視情況取代之環丙基' 視情況取代之環己基、祝 情況取代…基、視情況取代之喃唾基、視情況取代之 十朵基、視情況取代之萘基、視情況取代之料基、視情 況取代之㈣基、視情況取代之。答嗪基或視情 啉基； W不經，環戊基、視情況取代之環戊基、·環 丁基、環丁基、-C⑼·環己基或視情況取代之環己基取 代； R3不經-C(O)-環丙基取代； 127788.doc • 16 - 200840567 當R3為CH3或4·氯苯基曱基時，L_R1不為環丙基、環戊 基、視情況取代之環己基、-CH2·環己基、-NH-環己基、 -CH2CH2_環己基或視情況取代之吡唑基； 田丫為〇日守’ r3不為-(c〇-C4)烷基-視情況取代之異崎唑基 或視情況取代之11比σ坐基； 當L為（C^C：3)烷基時，R1不為視情況取代之異噚唑基； 當L為一鍵時，R1不為視情況取代之環丁基、視情況取 代之5衣己基、視情況取代之萘基、-CHy視情況取代之萘 • s、-ch2-cm見情％取代之萘基、才見,障況取代之吼唾基或 四氫苯并呋喃基； 該化合物不為R9 is hydrogen, optionally substituted (C,-C3)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted ( C3_C6)cycloalkyl; and η is 1, 2, 3 or 4; but the limiting condition is _c (〇l· optionally substituted furan R is not optionally substituted as a fluorenyl group or a base; R is not considered The situation is replaced by 啥琳基; R9 is not substituted by the cyclopropyl group as appropriate. The cyclohexyl group is replaced by the case, and the situation is replaced by the base, the sulphate is replaced by the case, and the ten bases are replaced as appropriate. a naphthyl group, optionally substituted, a substituting (iv) group, optionally substituted. Azinyl or an oxoyl group; W, a cyclopentyl group, optionally substituted cyclopentyl, Butyl, cyclobutyl, -C(9).cyclohexyl or optionally substituted cyclohexyl; R3 is not substituted by -C(O)-cyclopropyl; 127788.doc • 16 - 200840567 when R3 is CH3 or 4·chloro In the case of a phenylfluorenyl group, L_R1 is not a cyclopropyl group, a cyclopentyl group, an optionally substituted cyclohexyl group, -CH2.cyclohexyl group, -NH-cyclohexyl group, -CH2CH2_cyclohexyl group. Substituting the pyrazolyl group as appropriate; 丫 丫 ' ' 'r3 is not - (c〇-C4) alkyl - optionally substituted isosazolyl or optionally substituted 11 σ sitting; when L is When (C^C: 3) alkyl group, R1 is not an isoxazolyl group which is optionally substituted; when L is a bond, R1 is not a cyclobutyl group which is optionally substituted, and optionally substituted with 5 hexyl groups. Substituted naphthyl, -CHy optionally substituted naphthalene s, -ch2-cm see % substituted naphthyl, see, substituted oxime or tetrahydrobenzofuranyl; the compound is not

其中R3為視情況取代之哌嗪基或視情況取代之苯基·， 該化合物不為 —>4>γι 0-Ν 其中Rl為視情況取代之吨啶基或3 -氯笨基且_Y_R3為 -NH-C(〇)-視情況取代之苯基； -〇-視情況取代之吡啶基； 127788.doc -17· 200840567 ，NH_C(0)-0CH3 ; -CH2_視情況取代之哌嗪基； -〇-視情況取代之（CKC9)烷基； -CH2-嗎琳基；或 -O-C(O)-視情況取代之吡啶基； 但限制條件為該化合物不為Wherein R3 is optionally substituted piperazinyl or optionally substituted phenyl. The compound is not ->4>γι 0-Ν wherein R1 is optionally substituted oxaridinyl or 3-chlorophenyl and _ Y_R3 is -NH-C(〇)-substituted phenyl; -〇- optionally substituted pyridyl; 127788.doc -17· 200840567, NH_C(0)-0CH3 ; -CH2_ optionally substituted a pyridyl group; - 2-- optionally substituted (CKC9) alkyl; -CH2-morphinyl; or -OC(O)- optionally substituted pyridyl; but with the proviso that the compound is not

L為 CH2、ch(ch3)或 CH2CH2 ; Y為〇或CH2 ; 其中 R2 為 Η或 〇CH3 ·, R3 為 CH3 或 〇CF3 ;且 R為H或N02 ; 但限制條件為該化合物不為L is CH2, ch(ch3) or CH2CH2; Y is 〇 or CH2; wherein R2 is Η or 〇CH3 ·, R3 is CH3 or 〇CF3; and R is H or N02; but the limitation is that the compound is not

限制條件為化合物不為The restriction is that the compound is not

其中R1為苯基、4-氯苯基、 本Is明弟十五具體例係提供第十 中各取代基或視情況選用之取代 旅啶基或噻吩基。 第十四具體例之化合物，其 之取代基獨立為一 或多個汉1〇 127788.doc -18- 200840567 基，其中R1 G為視情況取代之烧基、烯基、視情況取代之 烧氧基、烧氧基烧氧基、烧氧基烧基、烧氧基魏基、烧氧 基幾基雜壤烧氧基、烧基、烧基胺基、烧基幾基、烧基 酯、烷基-O-C(O)-、烷基-雜環基、烷基-環烷基、烷基-腈、烷基磺醯基、炔基、醯胺基、胺基、胺基烷基、胺基 烷氧基、胺基羰基、曱腈、羰基烷氧基、甲醯胺基、cf3、 CN、-C(0)OH、-C(0)H、-C(0)-C(CH3)3、-OH、-C(0)0-烷基、-c(o)o-環烷基、-c(o)o-雜環基、-c(o)-烷基、 -C(O)-環烷基、-C(O)-雜環基、CN、環烷基、二烷基胺 基、二烧基胺基烧氧基、二烧基胺基幾基烧氧基、二烧基 胺基羰基、二烷基胺基磺醯基、-C(0)-0Ra、鹵素、雜環 基、雜環基烧基、雜環基氧基、經基、經基烧基、硝基、 侧氧基、苯基、-so2ch3、-so2cf3、磺醯基、四唑基、噻 吩基烷氧基、三氟甲基羰基胺基、三氟曱基磺醯胺基、雜 環基烷氧基、雜環基-S(0)p、環烷基_S(0)P、烷基-S-、雜 環基-S、雜環烷基、環烷基烷基、雜環基硫基、環烷基硫 基、N_烷基胺基及N，N-二烷基胺基，其中Ra為烷基、雜環 烷基或雜環基，且P為1或2。 本發明第十六具體例係提供具體例十四及十五之具有式 (IVa)之化合物：Wherein R1 is a phenyl group, a 4-chlorophenyl group, and the present is a specific example of the tenth substituent or, optionally, a substituted benzylidene group or a thienyl group. The compound of the fourteenth specific example, wherein the substituent is independently one or more of the group 1 127788.doc -18- 200840567, wherein R1 G is an optionally substituted alkyl group, an alkenyl group, optionally substituted for oxygen burning Alkoxy group, alkoxyalkyl group, alkoxyalkyl group, alkoxy group, alkoxy group, alkoxy group, alkoxy group, alkyl group, alkyl group, alkyl group, alkyl ester, alkane -OC(O)-, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkylsulfonyl, alkynyl, decylamino, amine, aminoalkyl, amine Alkoxy, aminocarbonyl, phthalonitrile, carbonyl alkoxy, formamidine, cf3, CN, -C(0)OH, -C(0)H, -C(0)-C(CH3)3 , -OH, -C(0)0-alkyl, -c(o)o-cycloalkyl, -c(o)o-heterocyclyl, -c(o)-alkyl, -C(O) -cycloalkyl, -C(O)-heterocyclyl, CN, cycloalkyl, dialkylamino, dialkylamino alkoxy, dialkylamino alkoxy, dialkyl Aminocarbonyl, dialkylaminosulfonyl, -C(0)-0Ra, halogen, heterocyclic, heterocyclyl, heterocyclyloxy, thiol, carbyl, nitro, Side oxy, phenyl, -so2ch3, -so2cf3, sulfonium , tetrazolyl, thienylalkoxy, trifluoromethylcarbonylamino, trifluoromethylsulfonylamino, heterocyclylalkoxy, heterocyclyl-S(0)p, cycloalkyl-S (0)P, alkyl-S-, heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl, heterocyclylthio, cycloalkylthio, N-alkylamino and N, N a dialkylamino group, wherein Ra is an alkyl group, a heterocycloalkyl group or a heterocyclic group, and P is 1 or 2. According to a sixteenth specific embodiment of the present invention, the compound of the formula (IVa) of the specific examples 14 and 15 is provided:

(IVa) 或其生理上可接受性鹽、溶劑化物、水合物或立體異構 I27788.doc -19- 200840567 物，其中： L為-鍵、·CH2Ch2.或（c3_C6)環烧基 之雜芳基或视情 R1為視情況取代之芳基、視情況取代 取代之-Ο-ΑΑ)燒基； 2 R為鹵素或CF3 ;且 3 R為直鏈或分支視情況取代 之（c3-c6)環燒基。 之（CrCs)烷基或視情況取代(IVa) or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, I27788.doc -19- 200840567, wherein: L is a bond, a CH2Ch2. or a (c3_C6) cycloalkyl group. Or Rx is optionally substituted aryl, optionally substituted - Ο-ΑΑ) alkyl; 2 R is halogen or CF3; and 3 R is linear or branched as appropriate (c3-c6) Ring-burning base. (CrCs) alkyl or substituted as appropriate

本發明第十七具體例提供具體例十四至十六之化合物， 其中R2為C1或CF3。 本發明第十八具體例提供具體例十四至十七之化合物， 其中R為C1。 本發明第十九具體例提供具體例十四至十八之具有式 (IVb)之化合物：The seventeenth embodiment of the present invention provides the compound of the specific examples fourteen to sixteen, wherein R2 is C1 or CF3. The eighteenth embodiment of the present invention provides the compound of the specific examples fourteen to seventeen, wherein R is C1. The nineteenth embodiment of the present invention provides the compound of the formula (IVb) of the specific examples 14 to 18:

R1 (IVb) 或其生理上可接受性鹽、溶劑化物、水合物、前藥 異構物或立體異構物，其中： 對映 L為一鍵、-CH2CH2-或（C3-C6)環貌基； R1為甲苯基、吡啶基、異呤唑基、吡嗪基、曱基吡嗪 基、乙酮基苯基、苯基、胺基曱酸第三丁_、苄腈、二乙 胺基苯基、嗟吩基、：甲基吼洛基、鹵基吼咬基或甲基吼 啶基；且 R3為異丁基、環丙基曱基、3-甲氡基丙基、1-乙基丙 127788.doc •20- 200840567 基、第二丁基、異丙基、第三丁基或三氟乙基。 本發明第二十具體例係提供具體例十四之具有下式 (IVc)之化合物：R1 (IVb) or a physiologically acceptable salt, solvate, hydrate, prodrug or stereoisomer thereof, wherein: the enantiomeric L is a bond, -CH2CH2- or (C3-C6) ring R1 is a tolyl group, a pyridyl group, an isoxazolyl group, a pyrazinyl group, a decylpyrazine group, an ethyl ketone phenyl group, a phenyl group, an amino decanoic acid tert-butyl group, a benzonitrile, a diethylamine group. Phenyl, porphinyl, methyl hydrazino, haloalkyl or methyl acridinyl; and R3 is isobutyl, cyclopropyl decyl, 3-methylmercaptopropyl, 1-B Propyl 127788.doc • 20- 200840567 base, second butyl, isopropyl, tert-butyl or trifluoroethyl. According to a twentieth embodiment of the present invention, there is provided a compound of the following formula (IVc):

或其生理上可接受性鹽、溶劑化物、水合物或立體異構 物，其中：Or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:

L為一鍵或-CH2CH2-; R為甲苯基、吼咬基、甲基σ比嗓基、苯基、胺基甲酸第 二丁酯、苄腈、嗟吩基、Ν·甲基π比u各基或鹵基吼σ定基；且 R3為異丁基、異丙基、環丙基曱基、3-甲氧基丙基、 乙基丙基、第二丁基或異丙基。 本發明第二十一具體例係提供第十二具體例之化合物， 其中R3為異丙基。 本發明弟二十二具體例係提供第二十及二--具體例之 化合物，其中R1為甲笨基或鹵基吨啶基。 本發明第二十三具體例係提供第二十至二十二具體例之 化合物，其中R1為氯D比啶基或氟吼啶基。 本發明第二十四具體例係提供一種醫藥組合物，其包括 如前述任一具體例之化合物或其醫藥可接受性鹽、溶劑化 物、水合物、代謝物、前藥、對映異構物或立體異構物， 及醫藥可接受性稀釋劑或載劑。 本發明第二十五具體例係提供一種治療免疫疾病之方 127788.doc -21 - 200840567 法，該方法包括對有需要之標的投與治療有效量之一气多 種前述任一具體例之化合物或其醫藥可接受性鹽、溶劑= 物、水合物、代謝物、前藥或立體異構物。 本發明第二十六具體例係提供第二十五具體例之方法， 其中該免疫疾病為自體免疫疾病。 本發明第二十七具體例係提供第二十六具體例之方法， 其中該自體免疫疾病為活動型慢性肝炎、阿迪森症 (Addison’s Disease)、抗-磷脂質症候群、特應性過敏、自 體免疫萎縮性胃炎、胃酸缺乏症（achl〇rhydra)自體免疫、 腹腔性疾病（Celiac Disease)、克隆氏症（Crohn，s Disease)、 克新氏症候群（Cushing’s Syndrome)、皮肌炎、古德帕斯策 症候群（Goodpasture’s Syndrome)、袼維氏症（Grave,s Disease)、橋本氏甲狀腺炎（Hashim〇t〇，s thyr〇iditis)、特發 性月上腺萎縮、特發性血小板減少症、蘭伯特-依頓症候 群（Lambert-Eaton Syndrome)、狼瘡樣肝炎、混合性結締 組織疾病、天皰瘡、尋常型天皰瘡、惡性貧血、水晶體原 性葡萄膜炎（phacogenic uveitis)、結節性多動脈炎、原發 性膽汁性肝硬化、原發性硬化性膽道炎、牛皮癬、雷諾氏 症候群（Raynauds Syndrome)、雷特氏症候群（Reiter，s Syndrome)、復發性多軟骨炎、斯密特氏症候群（Schmidt，sL is a bond or -CH2CH2-; R is a tolyl group, a thiol group, a methyl σ thiol group, a phenyl group, a second butyl carbamate, a benzonitrile, a porphinyl group, a Ν·methyl π ratio Each group or halo is 定σ-based; and R3 is isobutyl, isopropyl, cyclopropylindenyl, 3-methoxypropyl, ethylpropyl, t-butyl or isopropyl. A twenty-first embodiment of the present invention provides the compound of the twelfth embodiment, wherein R3 is an isopropyl group. The twenty-second specific example of the present invention provides a compound of the twentieth and second-specific examples, wherein R1 is a benzyl group or a halodonyl group. The twenty-third embodiment of the present invention provides the compound of the twenty-second to twenty-second specific examples, wherein R1 is chloro D-pyridyl or fluoroacridinyl. A twenty-fourth embodiment of the present invention provides a pharmaceutical composition comprising a compound according to any one of the above specific examples, or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer thereof Or a stereoisomer, and a pharmaceutically acceptable diluent or carrier. A twenty-fifth embodiment of the present invention provides a method for treating an immune disease 127788.doc -21 - 200840567, which comprises administering a therapeutically effective amount of a compound of any of the foregoing specific examples or a compound thereof Pharmaceutically acceptable salts, solvents = hydrates, metabolites, prodrugs or stereoisomers. A twenty-sixth embodiment of the present invention provides the method of the twenty-fifth embodiment, wherein the immune disease is an autoimmune disease. A twenty-seventh embodiment of the present invention provides the method of the twenty-sixth embodiment, wherein the autoimmune disease is active chronic hepatitis, Addison's Disease, anti-phospholipid syndrome, atopic allergy, Autoimmune atrophic gastritis, gastric acid deficiency (achl〇rhydra) autoimmune, celiac disease, Crohn's disease, Cushing's Syndrome, dermatomyositis, Goodpasture's Syndrome, Grave, s Disease, Hashim〇t〇, s thyr〇iditis, idiopathic adrenal atrophy, idiopathic platelets Reduced disease, Lambert-Eaton Syndrome, lupus-like hepatitis, mixed connective tissue disease, pemphigus, pemphigus vulgaris, pernicious anemia, phacogenic uveitis , nodular polyarteritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, Raynauds Syndrome, Reiter's syndrome (Reiter, s Syndrome), relapsing polychondritis, Schmidt's syndrome (Schmidt, s

Syndrome)、修格蘭氏症候群（Sj〇gren，s syndrome)、交感 性眼炎、南安氏動脈炎（Takayasu’s Arteritis)、顳動脈炎、 甲狀腺毒血症狼瘡、風濕症關節炎、B型胰島素抗性、潰 瘍性結腸炎、或偉格納氏肉芽腫（Wegener，s I27788.doc -22· 200840567 granulomatosis) 〇 本發明第二十八具體例係提供 包m m ^ τ /α蜃中樞神經系統疾 病之方去…法包括對有需要之標的投與治療有 一或多種具體例一至二十二夕外人 十一之化&物或其醫藥可 鹽、溶劑化物、水合物、祆谢犏二_ $ 代謝物、别藥、對映異構物或立 體異構物。Syndrome), Sj〇gren, s syndrome, sympathetic ophthalmia, Takayasu's Arteritis, temporal arteritis, thyroid toxemia, lupus, rheumatoid arthritis, type B insulin resistance Sexual, ulcerative colitis, or Wegener's granulomatosis (Wegener, s I27788.doc -22. 200840567 granulomatosis) 第二 The twenty-eighth specific example of the present invention provides a package of mm ^ τ /α蜃 central nervous system diseases The method of going to include the treatment of a subject in need thereof, one or more specific examples, one to twenty-two, an external human eleven, & or its medicinal salt, solvate, hydrate, 祆 犏 _ _ $ metabolite , other drugs, enantiomers or stereoisomers.

本發明第二十九具體例係提供—種治療多發性硬化症之 方法’該方法包括對有需要之標的投與治療有效量之一或 多種具體例一至二十三之化合物或其醫藥可接受性鹽、溶 劑化物、水合物、代謝物、前藥、對映異構物或立：異構 物。 特定具體例中，本發明提供下列化合物·· 3-(3-氯-4-環丙基甲氧基-苯基）-5-鄰_甲苯基嘮二 3-(4-丁氧基-3-氣-苯基）_5_鄰-甲笨基-[ι，2,4]π号二唑； 3-[3-氣-4-(1-甲基-環丙基曱氧基）_苯基扒5-鄰-曱苯基· [1，2,4]呤二唑； 3-[3-氯-4-(1-甲基-環丙基甲氧基）_苯基]鄰-甲苯基_ [1，2,4]崎二唑； 3-(3 -氯-4-戊氧基-苯基）-5-鄰-甲笨基-[1，2，4]p号二σ坐； 3-[3-氯·4-(3,3-二甲基-丁氧基）·苯基]-5-鄰-甲苯基_ [1，2,4]呤二唑； 3-(3-氯-4-環戊基甲氧基-苯基）-5-鄰-甲苯基-[ι，2,4ρ号二 127788.doc -23 - 200840567 3-[3-氯-4-(2-乙基-丁氧基）-苯基]-5-鄰-甲苯基-[1，2,4]嘮 二嗤； 3-(3-氯-4-辛氧基-苯基）-5-鄰-甲苯基-[1，2,4]崎二唑； 3-[3-氯-4-(3-甲氧基-丙氧基）-苯基]-5-鄰-甲苯基-[1，2,4]吟二唑； 3- [3-氯-4-(3-乙氧基-丙氧基）-苯基]-5-鄰-曱苯基-[1，2,4]嘮二唑；A twenty-ninth embodiment of the present invention provides a method for treating multiple sclerosis. The method comprises administering a therapeutically effective amount of one or more specific compounds of the first to the twenty-third of the compounds or a pharmaceutically acceptable amount thereof. Salts, solvates, hydrates, metabolites, prodrugs, enantiomers or stereoisomers. In a specific embodiment, the present invention provides the following compounds: 3-(3-chloro-4-cyclopropylmethoxy-phenyl)-5-o-tolylguanidinedi-3-(4-butoxy-3) - gas-phenyl)_5_o-methylphenyl-[ι,2,4]π-diazole; 3-[3- gas-4-(1-methyl-cyclopropyldecyloxy)-benzene 5-扒-曱-phenyl·[1,2,4]oxadiazole; 3-[3-chloro-4-(1-methyl-cyclopropylmethoxy)phenyl] ortho-toluene Base _ [1,2,4] oxadiazole; 3-(3-chloro-4-pentyloxy-phenyl)-5-o-methyl-phenyl-[1,2,4]p ; 3-[3-chloro-4-(3,3-dimethyl-butoxy)phenyl]-5-o-tolyl_[1,2,4]oxadiazole; 3-(3 -chloro-4-cyclopentylmethoxy-phenyl)-5-o-tolyl-[ι,2,4ρ号二127788.doc -23 - 200840567 3-[3-chloro-4-(2- Ethyl-butoxy)-phenyl]-5-o-tolyl-[1,2,4]indole; 3-(3-chloro-4-octyloxy-phenyl)-5- -tolyl-[1,2,4]soxadiazole; 3-[3-chloro-4-(3-methoxy-propoxy)-phenyl]-5-o-tolyl-[1, 2,4]oxadiazole; 3-[3-chloro-4-(3-ethoxy-propoxy)-phenyl]-5-o-indolephenyl-[1,2,4]fluorene Azole

1-{2-[2-氣-4-(5-鄰-曱苯基-[1，2,4]哼二唑-3-基）-苯氧基]-乙基}-旅σ定， 4- {2-[2-氯-4-(5-鄰-甲苯基-[1，2,4]崎二唑-3-基）-苯氧基]-乙基}-嗎琳； 3-(3 -氣- 4-¾戊氧基-苯基）-5-鄰-曱苯基- [1，2，4]p亏二σ坐； 3-[3-氣- 4- (1-乙基-丙氧基）-笨基]-5-鄰-甲苯基-[1，2,4] 口号 二口坐； 3-(3 -氣-4-¾己基氧基-苯基）-5-鄰-曱苯基-[1，2，4]0亏二 口坐； 3-(3-氣-4-苯乙基氧基-苯基）·5-鄰-甲苯基-[1，2，4]p号二 口坐； 3-[3 -氯-4-(3 -甲基-丁氧基）-苯基]-5-鄰-甲苯基-[1，2,4]口亏 二嗤； 3-(3-氯-4-環己基甲氧基-苯基）-5_鄰-曱苯基-[1，2,4]崎二 口坐； 3-[3-氣-4-(2 -異丙氧基-乙氧基）-苯基]-5-鄰-甲苯基_ [1，2,4]嘮二唑； 127788.doc -24- 200840567 3-(3-氯-4-戍-3-快基氧基-苯基）-5-鄰-甲苯基-[1，2,4]0号二 唑； 3-[3-氣-4-(2-噻吩-2-基-乙氧基）-苯基]-5-鄰-甲苯基-[1，2,4]嘮二唑； 3-(4-第二丁氧基-3-氯-苯基）-5-鄰-甲苯基-[1，2,4]噚二 口坐； {2-[2-氯-4-(5-鄰-甲苯基-[1，2,4]嘮二唑-3-基）-苯氧基]-丙 基卜二甲基-胺；1-{2-[2-Ga-4-(5-o-indolyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-ethyl}-Brigade 4-{2-[2-Chloro-4-(5-o-tolyl-[1,2,4]soxazol-3-yl)-phenoxy]-ethyl}-?-lin; 3- (3 - gas - 4-3⁄4 pentyloxy-phenyl)-5-o-indolephenyl-[1,2,4]p-deficient sigma sitting; 3-[3- gas- 4- (1-B -propyloxy)-phenyl]-5-o-tolyl-[1,2,4] sling two-spot; 3-(3- gas-4-3⁄4 hexyloxy-phenyl)-5- O-Phenylphenyl-[1,2,4]0 is a two-spot; 3-(3-Gas-4-phenylethyloxy-phenyl)·5-o-tolyl-[1,2, 4] p-two sitting; 3-[3-chloro-4-(3-methyl-butoxy)-phenyl]-5-o-tolyl-[1,2,4] ; 3-(3-chloro-4-cyclohexylmethoxy-phenyl)-5-o-indolephenyl-[1,2,4]: two-seat; 3-[3- gas-4-( 2-isopropoxy-ethoxy)-phenyl]-5-o-tolyl_[1,2,4]oxadiazole; 127788.doc -24- 200840567 3-(3-chloro-4- Indole-3-yloxy-phenyl)-5-o-tolyl-[1,2,4]oxodiazole; 3-[3- gas-4-(2-thiophen-2-yl- Ethoxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole; 3-(4-secondbutoxy-3-chloro-phenyl)-5- O-tolyl-[1,2,4]噚 two-seat; {2-[2-chloro-4-(5-o-tolyl-[1,2,4]oxadiazol-3-yl) -phenoxy]-propyldidimethyl-amine;

{2-[2-氣-4-(5-鄰-曱苯基-[1，2,4]喝二唑-3-基）-苯氧基]-乙 基}-二甲基-胺； 3-(3 -氣-4-環丁基甲氧基-苯基）-5-鄰-曱苯基-[1，2，4]p亏二 唑； 3-{4-[((E)-丁-2·細基）氧基]-3-氯-苯基}-5-鄰-曱苯基-[1，2,4]噚二唑； 3-[3-氯-4-(4,4,4-二氣-丁氧基）-苯基]-5-鄰-甲苯基-[1，2,4]嘮二唑； 3-[3 -鼠-4-(4-甲基-¾己基曱氧基）-苯基]-5 -鄰-甲苯基_ [1，2,4]呤二唑； 2- [3-(3-氣-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5-基]-吼 嗪； 3- (3-氯-4-異丙氧基-苯基）-5-異噚唑-3-基-[1，2,4]嘮二 唑； 3·(3 -氯-4-異丙氧基-苯基）-5-(2-甲氧基-乙基）·[1，2,4]^ 127788.doc -25- 200840567 4-[3-(3-氣-4-異丙氧基-苯基）-[1，2,4]崎二唑-5-基]-口比 啶； 3-(3-氯-4-異丙氧基-苯基）-5-環丙基甲基-[1，2,4]崎二 口坐； 3·[3-(3 -氣-4-異丙乳基-苯基）-[1，2,4]p亏二。坐-5 -基]-°比 口定； 2- [3-(3-氣-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5-基]-吼 口定； 3- (3-氣-4-異丙氧基-苯基）-5-鄰-甲苯基-[1，2,4]ρ亏二σ坐； 4- [3-(3-氯-4-異丙氧基-苯基）-[1，2,4]咩二唑-5-基]-3-甲 基-σ比ϋ定， 3,5-雙-(3_氯-4-異丙氧基-苯基）-[1，2,4]哼二唑； [3-(3-氣-4-異丙氧基-苯基Hl，2,4]噚二唑-5-基]-二甲基-胺； 5- 苄基-3-(3_氯-4-異丙氧基-苯基）-[1，2,4]崎二唑； 3·(3-氯-4-異丙氧基-苯基）-5-苯基-[1，2,4]嘮二唑； 3- [3-(3-氣-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5-基甲基]-比σ定； 4- {2-[3-(3-氯-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5_基]-乙 基}-吨σ定， 3-(3-氣-4-異丙氧基-苯基）-5-(3-二氟甲基-苯基）_ [1，2,4]呤二唑； 3-(3 -氯-4-異丙氧基-苯基）-5-( 3 -甲基-丁基）-[1，2,4]。亏二 127788.doc -26- 200840567 3-(3-氣-4-異丙氧基-苯基）-5-(2,2-二甲基-丙基）-[1，2,4]吟 .唑； 3-(3 -氣-4-異丙氧基-苯基）-5 -己基- 3-(3-氣-4-異丙氧基-苯基）-5-(3,3,3-三氟-丙基）-[1，2,4]嘮 3-(3-氯-4-異丙氧基-苯基）-5-甲氧基曱基-[1，2,4]崎二 口坐；{2-[2-Ga-4-(5-o-indolephenyl-[1,2,4]doxadiazol-3-yl)-phenoxy]-ethyl}-dimethyl-amine; 3-(3- gas-4-cyclobutylmethoxy-phenyl)-5-o-indolephenyl-[1,2,4]p-deficiazole; 3-{4-[((E)-butyl -2· fine base)oxy]-3-chloro-phenyl}-5-o-indolephenyl-[1,2,4]oxadiazole; 3-[3-chloro-4-(4,4 ,4-dioxa-butoxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole; 3-[3 -mur-4-(4-methyl-3⁄4-hexyl)曱oxy)-phenyl]-5-o-tolyl_[1,2,4]oxadiazole; 2-[3-(3- gas-4-isopropoxy-phenyl)-[1 , 2,4]oxadiazol-5-yl]-pyridazine; 3-(3-chloro-4-isopropoxy-phenyl)-5-isoxazol-3-yl-[1,2, 4] oxadiazole; 3·(3-chloro-4-isopropoxy-phenyl)-5-(2-methoxy-ethyl)·[1,2,4]^ 127788.doc -25 - 200840567 4-[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-perpenopyridine; 3-(3-Chloro- 4-isopropoxy-phenyl)-5-cyclopropylmethyl-[1,2,4] Saki sitting; 3·[3-(3- gas-4-isopropyllacyl-phenyl) )-[1,2,4]p is two. Sit 5--5-based]-° ratio; 2-[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-oxime 3-(3-Actyl-4-isopropoxy-phenyl)-5-o-tolyl-[1,2,4]ρ亏二σ; 4- [3-(3-Chlorine -4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-σ ratio, 3,5-bis-(3_chloro-4 -isopropoxy-phenyl)-[1,2,4]oxadiazole; [3-(3- gas-4-isopropoxy-phenyl Hl,2,4]oxadiazole-5- 5-dimethyl-amine; 5-benzyl-3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]soxadiazole; 3·(3-chloro- 4-isopropoxy-phenyl)-5-phenyl-[1,2,4]oxadiazole; 3-[3-(3- gas-4-isopropoxy-phenyl)-[1 , 2,4]oxadiazol-5-ylmethyl]-pyrazine; 4-{2-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4 Oxazol-5-yl]-ethyl}-ton sigma, 3-(3-aluminum-4-isopropoxy-phenyl)-5-(3-difluoromethyl-phenyl)_ [1,2,4]oxadiazole; 3-(3-chloro-4-isopropoxy-phenyl)-5-(3-methyl-butyl)-[1,2,4]. Two 127788.doc -26- 200840567 3-(3-Gas-4-isopropoxy-phenyl)-5-(2,2-dimethyl-propyl)-[1,2,4]吟. Azole; 3-(3- gas-4-isopropyl -Phenyl)-5-hexyl-3-(3-cyclo-4-isopropoxy-phenyl)-5-(3,3,3-trifluoro-propyl)-[1,2,4唠3-(3-chloro-4-isopropoxy-phenyl)-5-methoxyindolyl-[1,2,4]

3-(3-氣-4-異丙氧基-苯基）-5-甲基硫基甲基-[1，2,4]噚二 嗤； 3-(3-氯-4-異丙氧基-苯基）-5-乙氧基甲基-[1，2,4]噚二 唾； 3-(3 -氣-4-異丙氧基-苯基）-5-(2-甲乳基-乙乳基甲基）_ [1，2,4]哼二唑； 3-(3 -氣-4-異丙乳基-苯基）-5-(四鼠-σ夫喃-2 -基）-[1，2,4] 口亏 二口坐； 3-(3 -氯-4-異丙氧基-苯基）-5·(四鼠夫喃-3 -基）-[1，2,4]口亏 二峻； 3-(3 -氣-4-異丙乳基-苯基）-5-¾丙基-[1，2，4 ] 0亏二σ坐， 3-(3 -氣-4-異丙氧基-苯基）-5-¾ 丁基-[1，2，4]ρ亏二ϋ坐， 3-(3-氣-4-異丙氧基-苯基）-5-環戊基_[1，2,4]嘮二唑； 3-(3-氯-4-異丙氧基-苯基）-5-環戊基甲基-[1,2,4]噚二 口坐； 3-(3-氣-4-異丙氧基-苯基）-5-環己基-[1，2,4]噚二唑； 3-(3-氯-4-異丙氧基-苯基）-5-環己基甲基-[1，2,4]嘮二 127788.doc -27- 200840567 3-(3 -氯-4 -異丙氧基-苯基）-5-(1-曱基-環丙基）-[1，2,4]口亏 二口坐； 3-(3 -氣-4-異丙氧基-苯基）-5-(2-甲基-ί哀丙基）-[1，2,4]0亏 二口坐； 3-(3 -氯-4 -異丙氧基-苯基）-5-(2-乙氧基-乙基）-[1，2,4] 口亏 二嗤；3-(3-Actyl-4-isopropoxy-phenyl)-5-methylthiomethyl-[1,2,4]indole; 3-(3-chloro-4-isopropoxy -Phenyl)-5-ethoxymethyl-[1,2,4]indole; 3-(3- gas-4-isopropoxy-phenyl)-5-(2-methyl milk -ethylidylmethyl)_[1,2,4]oxadiazole; 3-(3- gas-4-isopropyllacyl-phenyl)-5-(four-rat-suffran-2) Base)-[1,2,4] sip in the mouth; 3-(3-chloro-4-isopropoxy-phenyl)-5·(tetramf-folly-3-yl)-[1, 2,4] sin deficiency; 3-(3- gas-4-isopropyllacyl-phenyl)-5-3⁄4 propyl-[1,2,4 ] 0 sigma sigma, 3-(3 - gas-4-isopropoxy-phenyl)-5-3⁄4 butyl-[1,2,4]ρ亏二ϋ, 3-(3-, 4-isopropoxy-phenyl) -5-cyclopentyl-[1,2,4]oxadiazole; 3-(3-chloro-4-isopropoxy-phenyl)-5-cyclopentylmethyl-[1,2,4噚 two sitting; 3-(3-a-4-isopropoxy-phenyl)-5-cyclohexyl-[1,2,4]oxadiazole; 3-(3-chloro-4-iso Propoxy-phenyl)-5-cyclohexylmethyl-[1,2,4]indole 127788.doc -27- 200840567 3-(3-chloro-4-isopropoxy-phenyl)-5 -(1-indolyl-cyclopropyl)-[1,2,4] sip in the mouth; 3-(3- gas-4-isopropoxy- 5-(3-methyl- lysyl)-[1,2,4]0 is a two-spot; 3-(3-chloro-4-isopropoxy-phenyl)-5- (2-ethoxy-ethyl)-[1,2,4]

(S)-5[3-(3 -氣-4-異丙氧基-苯基）-[1，2,4]p亏二°坐-5 -基]-口比 咯啶-2-酮； (R)-5[3-(3·氣-4-異丙乳基-苯基）-[1，2,4]u号二峻-5-基]-10比 咯啶-2-酮； 5 -节基氧基甲基- 3- (3 -氯-4 -異丙氧基-苯基）-[1，2,4] p号二 口坐； 3-(3 -氯-4 -異丙氧基-苯基）-5-(1-苯基-環丙基）-[1，2，4]0亏 二口坐； 3-(3-氯-4-異丙氧基-苯基）-5-((S)-l-苯基-丙基）-[l，2,4]p亏 二口坐； 3-(3 -氣-4·異丙氧基-苯基）-5-(3-苯基-丙基）-[1，2,4]p亏二 口坐； 3-(3 -氯-4 -異丙氧基-苯基）-5-((R)-甲氧基-苯基-甲基）* [1，2,4]嘮二唑； 3-(3-氯-4-異丙氧基-苯基）-5-((8)-曱氧基-苯基-甲基）-[1，2,4]崎二唑； 3-(3 -氯-4-異丙氧基-苯基）-5-(2-苯乳基-乙基）-[1，2,4]口亏 127788.doc -28- 200840567 呋喃-2-曱酸[3-(3-氣-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5-基甲基]-酿胺； 3-(3-氣-4-異丙氧基-苯基）-5-(3- σ塞吩-2-基-丙基）_ [1，2,4]嘮二唑； ^{443-(3-氣-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5-基]-哌 。定-1 -基}-乙嗣， 3-(3-氣-4-異丙氧基-苯基）-5-(3,5-二氣-节基）-[1，2,4]0亏二 唑； 3-[3-(3 -氣-4-異丙氧基-苯基）-[1，2,4]p亏二嗤-5 -基]-1-苯 基丙焼* -1-嗣， 3-(3 -氯-4 -異丙氧基-苯基）-5-(3 -苯氧基-丙基）-[1，2，4]1:7号 二口坐； 3- [3-(3-氣·4-異丙氧基-苯基）-[1，2,4]吟二唑-5-基]-1-噻 吩-2 -基-丙烧-1 - ί同， 4- [3-(3-氯-4-異丙氧基-苯基）-[1，2,4]呤二唑-5-基]-Ν-苯 基-丁醯胺； Ν-[3-(3 -氣-4 -異丙氧基-苯基）-[1，2,4]/亏二嗤-5-基甲基]_ 4 -甲基-笨石黃酿胺， 1-{4-[3-(3 -氣-4-異丙氧基-苯基）-[1，2,4]ρ亏二嗤-5-基]-苯 基}-乙酮； {4-[3-(3-氣-4-異丙氧基-苯基）-[1，2,4]嘮二唑-5-基]-苯 基}-二乙基-胺；與三氟乙酸之化合物； 3-(3-氯-4-異丙氧基-苯基）-5-乙基-[1，2,4]噚二唑； 127788.doc -29- 200840567 3 - (3 -氣-4 -異丙氧基-苯基）-5 -丙基-[1，2，4 ]p亏二ϋ坐； 3-(3 -氣-4-異丙氧基-苯基）· 5-異丙基- [1,2，4]0亏二哇； 5-丁基-3-(3-氯-4-異丙氧基-苯基）-[1，2,4]>号二唑； 5-第二丁基-3-(3 -氯-4 -異丙氧基-苯基）-[1，2,4]p亏二σ坐； 3-(3-氯-4-異丙氧基-苯基）-5-異丁基-[1，2,4]噚二唑； 3-(3 -氣-4-異丙氧基-苯基）-5 -戊基-[1，2，4]p亏二σ坐； {4-[3-(3 -氯-4-異丙氧基-苯基）-[1，2,4]ρ亏二峻-5-基]•苯 基}_胺基曱酸第三丁酯； 3- [3-(3 -氣-4-異丙氧基-苯基）-[1，2,4]0亏二。坐-5-基]-卡 腈； 4- [3-(3-氯-4-異丙氧基-苯基）-[1，2,4]呤二唑-5-基]-苄 腈； {3-[3-(3 -氯-4-異丙氧基-苯基）41,2,4]11亏二嗤-5 -基]-苯 基}-二甲基-胺， 5 -聯苯-4-基曱基- 3- (3 -氣-4-異丙氧基-苯基）-[1，2,4]p号二 嗤； • {4-[3-(3-氯-4-異丙氧基-苯基）-[1，2,4]崎二唑-5-基曱基]- 苯基}-二甲基-胺， 3-(3 -氯-4-異丙氧基-苯基）-5-(4-苯氧基-节基）-[1，2,4]。亏 二嗤； 5- (4-节基氧基-节基）-3-( 3-氯-4-異丙氧基-苯基）_ [1，2,4]崎二唑； 3-(3-氯-4-異丙氧基-苯基）-5-萘-1-基甲基-[1，2,4]噚二 127788.doc -30- 200840567 3-(3-氯-4-異丙氧基-苯基）-5-萘-2-基甲基-[1，2,4]噚二 口坐； 3-(3-氣-4-異丙氧基-苯基）-5-呋喃-2-基-[1，2,4]崎二唑； 3-(3 -氣-4-異丙氧基-苯基）-5 -ϋ夫喃-3-基-[1，2，4]p亏二嗤， 3-(3-氯-4-異丙氧基-苯基）-5-噻吩-2-基-[1，2,4]吟二唑； 3-(3-氣-4-異丙氧基-苯基）-5-噻吩_3-基-[1，2,4]崎二唑； 3-(3 -氣-4-異丙氧基-苯基）-5-(1-甲基-1Η -11比洛-2 -基） [1，2,4]嘮二唑； φ 3-(3-氯-4-異丙氧基-苯基）-5-噻唑-4-基-[1，2,4]喝二唑； 3-(3 -氣-4-異丙氧基-苯基）-5-(3，5 -二甲基-異17亏17坐-4·基）_ [1，2,4]4二唾； 2- [3-(3 -氣-4 -異丙氧基-苯基）-[1，2,4]。号二吐-5 -基]-5 -甲 基-吼σ秦， 3- [3-(3-氣-4-異丙氧基-苯基）-[1，2,4]崎二唑-5-基]-6,7-二 鼠-5 Η -苯并ϋ夫喃-4 -明， 4- [3-(3-氣-4-異丙氧基-苯基）-[1，2,4]崎二唑-5-基甲基]- 鲁 嗎琳； 3 -氣-4-[3-(3 -氣-4-異丙氧基-苯基）-11,2,4]17亏二。坐-5-基]· 吼咬； 3- (3-氯-4-異丙氧基-苯基）-5-(3-氯-苯基）-[1，2,4]嘮二 唑； 4- [3-(3-氯-4-異丙氧基-苯基）-[1，2,4]噚二唑-5-基]-3-氟-吼σ定； 2-氣-4-[3-(3-氣-4-異丙氧基-苯基）-[1，2,4]崎二唑-5-基]- 127788.doc -31 - 200840567 σ比咬； 4-[3-(3-氣-4-異丙氧基-苯基）-[1，2,4]吟二唑-5-基]-2-氟- 吼咬； 4- [3-(3-氯-4-異丙氧基-苯基）-[1，2,4]吟二唑-5-基]-喹 啉； 2,6-二氯-4-[3-(3-氯-4-異丙氧基-苯基）-[1，2,4]吟二唑-5-基]-°比σ定， 3-(3 -氣-4-異丙氧基-5-甲氧基-苯基）-5 -苯基-[1，2,4]。亏二 〇坐； ^-[^-^-氣-心異丙氧基^-甲氧基-苯基）-!^，〗，^·]^^:^^-基]-0比σ定， 2- 甲氧基-5-(5-苯基-[1，2,4]嘮二唑-3-基）j比啶； 5- (5-吡啶-4-基-[1，2,4]嘮二唑-3-基）-2-(2,2,2-三氟-乙氧 基）-σ定， 5-(5-苯基-[l，2,4]r号二唑-3-基）-2-(2,2,2-三氟-乙氧基）-口比 啶； 5-(3-氯吼啶-4-基）-3-(6-(2,2,2-三氟乙氧基）吼啶-3-基）-1，2,4-口咢二 口坐； 5-(3-甲基吡啶-4-基）-3-(6-(2,2,2-三氟乙氧基）吡啶-3-基）-1，2,4-崎二。坐； 3- (4-第三丁基-苯基）-5-鄰-甲苯基-[1，2,4]崎二唑； 3-(3-氯-4-甲基-苯基）-5-鄰-甲苯基-[1，2,4]吟二唑； 3-(4-乙基-苯基）-5-鄰-曱苯基-[1，2,4]呤二唑； 3-(4-丁基-苯基）-5-鄰-甲苯基-[1，2,4]呤二唑； 127788.doc -32- 200840567 M4-異丙基·苯基）-5-鄰-曱苯基41,2,4]噚二唑； 4-(3-苯基-[1，2,4]吟二唑-5-基)-吡啶； 4-[3-(3•氯-苯基）-[1，2,4]号二吐-5-基]·σ比变； 4_(5-吡啶-4-基-[1，2,4]噚二唑-3-基）-苯酚； 3-苯并呋喃-5-基-5-鄰-曱苯基_[ι，2,4]噚二唑； 3 (4甲氧基-3-二氟曱基-苯基）_5_鄰-曱苯基-[1，2，4] 口号二 口坐； 3-聯苯-4-基-5-鄰-甲苯基-[12,4]吟二唑； 3-(3-氣-4-異丙氧基-苯基）·5_(2,4-二氣-苯基）_[ι，2,4]嘮二 嗤； 或其醫藥可接受性鹽、溶劑化物、水合物、代謝物、前 藥、對映異構物或立體異構物。 本發明另一態樣係提供一種醫藥組合物，其包括一或多 種式（I)、（la)、（π)、（m)、（IV)、（IVa)及（IVb)之化合物、 或其醫藥可接受性鹽、溶劑化物、水合物、代謝物、前藥 或立體異構物以及醫藥可接受性稀釋劑或載劑。本發明較 佳態樣係提供一種醫藥組合物，其中該化合物或該等化合 物係以治療有效量存在。本發明相關態樣係提供一種醫藥 組合物，其中該化合物或該等化合物係以預防有效量存 在。 本發明又另一態樣係提供一種經包裝之醫藥，其包括一 或多種式⑴、（la)、（II)、（III)、（IV)、（1%)及（IVb)之化合 物、或其醫藥可接受性鹽、溶劑化物、水合物、代謝物、 别藥或立體異構物以及用途指示。本發明之一具體例係提 127788.doc -33- 200840567 供-種經包裝之醫藥，其中該化合物或該等化合物係以治 療有效量存在。本發明另一態樣係提供一種經包裝之醫 藥，其中該化合物或該等化合物係以預防有效量存在。 【實施方式】 本發明中使用下列定義： ’’治療有效量”為可抑制（全部或部分）症狀之進展、或減 輕（至少部份）症狀之一或多種病徵之式⑴、（⑷、（ib)或(S)-5[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]p-deficient s--5-yl]-perylpyridin-2-one (R)-5[3-(3·Ga-4-isopropyllacyl-phenyl)-[1,2,4]u bis--5-yl]-10-pyridin-2-one ; 5 - benzyloxymethyl-3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4] p-didentate; 3-(3-chloro-4- Isopropoxy-phenyl)-5-(1-phenyl-cyclopropyl)-[1,2,4]0 succinimide; 3-(3-chloro-4-isopropoxy-benzene 5-(3-(3-)-isopropenyl-propyl)-[l,2,4]p 5-(3-phenyl-propyl)-[1,2,4]p is a two-spot; 3-(3-chloro-4-isopropoxy-phenyl)-5-((R)- Methoxy-phenyl-methyl)*[1,2,4]oxadiazole; 3-(3-chloro-4-isopropoxy-phenyl)-5-((8)-decyloxy -phenyl-methyl)-[1,2,4]soxadiazole; 3-(3-chloro-4-isopropoxy-phenyl)-5-(2-phenyllacyl-ethyl)- [1,2,4] loss 127788.doc -28- 200840567 furan-2-furic acid [3-(3-gas-4-isopropoxy-phenyl)-[1,2,4]唠2 Zyrid-5-ylmethyl]-bristamine; 3-(3-a-4-isopropoxy-phenyl)-5-(3- σ-sept-2-yl-propyl)-[1, 2,4]oxadiazole; ^ {443-(3-Gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin. -1 -yl}-acetamidine, 3-(3-cyclo-4-isopropoxy-phenyl)-5-(3,5-di-gas-based)-[1,2,4]0 Bis-diazole; 3-[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]p-deficidin-5-yl]-1-phenylpropanthene* 1-嗣, 3-(3-chloro-4-isopropoxy-phenyl)-5-(3-phenoxy-propyl)-[1,2,4]1:7: 3-[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-1-thiophen-2-yl-propanone-1 -同, 4-[3-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-indole-phenyl-butanamine; -[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]/defindol-5-ylmethyl]_4-methyl-phenyl stearamine 1-{4-[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]p-dioxan-5-yl]-phenyl}-ethanone; {4 -[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-phenyl}-diethyl-amine; with trifluoroacetic acid a compound; 3-(3-chloro-4-isopropoxy-phenyl)-5-ethyl-[1,2,4]oxadiazole; 127788.doc -29- 200840567 3 - (3 - gas -4 -isopropoxy-phenyl)-5-propyl-[1,2,4 ]p dioxin; 3-(3- gas-4-isopropoxy-phenyl)· 5- different Propyl-[1,2,4]0 yttrium; 5-butyl-3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]>; 5-t-butyl-3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]p-deficient sigma; 3-(3-chloro-4-isopropyl Oxy-phenyl)-5-isobutyl-[1,2,4]oxadiazole; 3-(3- gas-4-isopropoxy-phenyl)-5-pentyl-[1, 2,4]p deficiency sigma sitting; {4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]ρ亏二峻-5-yl]•benzene Tertyl}-aminobutyric acid tert-butyl ester; 3-[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]0. Sodium-5-yl]-carbonitrile; 4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile; {3-[3-(3-Chloro-4-isopropoxy-phenyl)41,2,4]11 bis-indol-5-yl]-phenyl}-dimethyl-amine, 5-linked Benzyl-4-ylindolyl-3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]p-diindole; • {4-[3-(3-chloro- 4-isopropoxy-phenyl)-[1,2,4]soxazol-5-ylindenyl]-phenyl}-dimethyl-amine, 3-(3-chloro-4-isopropyl Oxy-phenyl)-5-(4-phenoxy-benzyl)-[1,2,4]. Deficient bismuth; 5-(4-hydroxy-4-aryl-phenyl)-3-[3-chloro-4-isopropoxy-phenyl)_[1,2,4]soxadiazole; 3-( 3-chloro-4-isopropoxy-phenyl)-5-naphthalen-1-ylmethyl-[1,2,4]indole 127788.doc -30- 200840567 3-(3-chloro-4- Isopropoxy-phenyl)-5-naphthalen-2-ylmethyl-[1,2,4]indole; 3-(3-a-4-isopropoxy-phenyl)-5 -furan-2-yl-[1,2,4]soxadiazole; 3-(3- gas-4-isopropoxy-phenyl)-5-furfuran-3-yl-[1,2 , 4]p-deficient, 3-(3-chloro-4-isopropoxy-phenyl)-5-thiophen-2-yl-[1,2,4]oxadiazole; 3-(3- Gas-4-isopropoxy-phenyl)-5-thiophene-3-yl-[1,2,4]soxadiazole; 3-(3- gas-4-isopropoxy-phenyl)- 5-(1-methyl-1Η-11-pyrylene-2-yl)[1,2,4]oxadiazole; φ 3-(3-chloro-4-isopropoxy-phenyl)-5- Thiazol-4-yl-[1,2,4]dioxadiazole; 3-(3- gas-4-isopropoxy-phenyl)-5-(3,5-dimethyl-iso 17-depleted 17 Sit-4.yl)_[1,2,4]4disal; 2-[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]. No.2 -5-yl]-5-methyl-吼σ Qin, 3-[3-(3- gas-4-isopropoxy-phenyl)-[1,2,4] oxadiazole- 5-yl]-6,7-di-rham-5-indole-benzofuran-4-min, 4-[3-(3- gas-4-isopropoxy-phenyl)-[1,2 , 4] Soxadiazol-5-ylmethyl]-Luberin; 3-Gas-4-[3-(3-Ga-4-isopropoxy-phenyl)-11,2,4]17 Loss two. Sit-5-yl]·bite; 3-(3-chloro-4-isopropoxy-phenyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole; 4-[3-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-fluoro-indolozine; 2-gas-4 -[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]- 127788.doc -31 - 200840567 σ ratio bite; 4-[ 3-(3-Actyl-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-2-fluoro-bite; 4-[3-(3-chloro -4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-quinoline; 2,6-dichloro-4-[3-(3-chloro-4- Isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-° ratio σ, 3-(3- gas-4-isopropoxy-5-methoxy- Phenyl)-5-phenyl-[1,2,4]. -二〇坐; ^-[^-^-gas-heart isopropoxy^-methoxy-phenyl)-!^, 〗, ^·]^^:^^-基]-0 ratio σ , 2-methoxy-5-(5-phenyl-[1,2,4]oxadiazol-3-yl)j-pyridinyl; 5-(5-pyridin-4-yl-[1,2, 4]oxadiazol-3-yl)-2-(2,2,2-trifluoro-ethoxy)-sigrodidine, 5-(5-phenyl-[l,2,4]r-diazole 3-yl)-2-(2,2,2-trifluoro-ethoxy)-perpenopyridine; 5-(3-chloroacridin-4-yl)-3-(6-(2,2) , 2-trifluoroethoxy) acridine-3-yl)-1,2,4-mouth sputum; 5-(3-methylpyridin-4-yl)-3-(6-(2 , 2,2-Trifluoroethoxy)pyridin-3-yl)-1,2,4-Saki. 3-(4-tert-butyl-phenyl)-5-o-tolyl-[1,2,4]soxadiazole; 3-(3-chloro-4-methyl-phenyl)- 5-o-tolyl-[1,2,4]oxadiazole; 3-(4-ethyl-phenyl)-5-o-indolephenyl-[1,2,4]oxadiazole; 3 -(4-butyl-phenyl)-5-o-tolyl-[1,2,4]oxadiazole; 127788.doc -32- 200840567 M4-isopropylphenyl)-5-o- Phenylphenyl 41,2,4]oxadiazole; 4-(3-phenyl-[1,2,4]oxadiazol-5-yl)-pyridine; 4-[3-(3•chloro-benzene) Base)-[1,2,4]dioxa-5-yl]·σ ratio change; 4_(5-pyridin-4-yl-[1,2,4]oxadiazol-3-yl)-phenol 3-benzofuran-5-yl-5-o-indolephenyl-[ι,2,4]oxadiazole; 3 (4methoxy-3-difluoroindolyl-phenyl)_5_ -曱Phenyl-[1,2,4] Slogan two sitting; 3-biphenyl-4-yl-5-o-tolyl-[12,4]oxadiazole; 3-(3-gas-4 -isopropoxy-phenyl)·5_(2,4-dioxa-phenyl)_[ι,2,4]indole; or a pharmaceutically acceptable salt, solvate, hydrate or metabolite thereof , prodrug, enantiomer or stereoisomer. Another aspect of the present invention provides a pharmaceutical composition comprising one or more compounds of the formula (I), (la), (π), (m), (IV), (IVa) and (IVb), or A pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier. A preferred aspect of the invention provides a pharmaceutical composition wherein the compound or the compounds are present in a therapeutically effective amount. A related aspect of the invention provides a pharmaceutical composition wherein the compound or the compounds are present in a prophylactically effective amount. Yet another aspect of the present invention provides a packaged medicament comprising one or more compounds of the formulae (1), (la), (II), (III), (IV), (1%) and (IVb), Or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, other drug or stereoisomer thereof, and instructions for use. A specific embodiment of the invention is 127788.doc-33-200840567 for a packaged medicament wherein the compound or the compounds are present in a therapeutically effective amount. Another aspect of the invention provides a packaged medicament wherein the compound or compounds are present in a prophylactically effective amount. [Embodiment] The following definitions are used in the present invention: ''Therapeutically effective amount' is a formula (1), ((4), () that can inhibit (in whole or in part) the progression of symptoms, or alleviate (at least part of) one or more symptoms. Ib) or

(Ic)化合物或二或多種該等化合物之組合物的量。治療有 效量亦可為預防上有效之量。治療有效之量將取決於病患 之體型及性別、欲處置之症狀、症狀之嚴重性及觀察之結 果針對既疋之病患，治療有效量可藉熟悉本技藝者已知 之方法決定。 生理上可接又性鹽”係指保有游離鹼之生理效力及性質 且、、二由與無機酸例如鹽酸、氫溴酸、硫酸、硝酸及磷酸， 或與有機酸如績酸H有機填酸、甲烧磺酸、乙烧績 西夂對-甲苯石頁酸、檸檬酸、富馬酸、馬來酸、號轴酸、 苯甲酸、水楊酸、乳酸、酒石酸（例如㈩或酒石酸或其 此。物）、胺基酸（例如（+)或㈠·胺基酸或其混合物）筝反應 獲得之該等鹽類。此等鹽可藉由熟悉本技藝者已知之方法 具有酸性取代基之某些式⑴、㈣、（11)、⑽、（IV)、 (Va)或（ivb)之化合物可以與醫藥可接受性鹽之鹽存在。 本务明包含该等鹽。該等鹽之實例包含鈉鹽、钾鹽、離胺 酸鹽及精胺酸鹽。此等鹽可藉由熟悉本技藝者已知之方法 127788.doc -34. 200840567 製備。 某些式（I)、（ia)、（II)、（III)、（IV)、（IVa)或（IVb)之化合 物及其鹽可以一種以上之結晶形式存在，且本發明包含該 結晶形式及其混合物。 某些式（1)、（Ia)、（11)、（ΙΠ)、（IV)、（IVa)或（IVb)之化合 物及其鹽亦可以溶劑化物，例如水合物之形式存在，且本 發明包含該溶劑化物及其混合物。 某些式（I)、（la)、（II)、（111)、（IV)、（IVa)或（IVb)之化合 物可=有-或多個對掌中心，且以不同之光學活性形式存 在i 當式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)之化合 物3有個董|掌中心、，則該化合物卩二種對映異構之形式 存：且本發明包含對映異構物及對映異構物之混合物如消 疋心口物兩者。對映異構物可藉由熟悉本技藝者已知之方 去：析，例如藉由形成可藉由例如結晶分離之非對映異構 之鹽；形成可藉由例如結晶、氣·液或液態層析分離之非 子映異構衍生物或錯合物；使—種對映異構物與對映显構 ^特異之試劑進行選擇性反應’例如酵素醋化作用；或 在對掌性環境下例如在對掌性立# 1 士且 〆 旱性支撐材例如具有結合對掌性 =體之氧切或在對掌性溶劑存在下，經氣_液或 :。應了解當所需之對映異構物藉由上述分離程序之一 映=化學實體時，可使用另一步驟以釋出所需之對 劑:、基Τ二Γ可藉由不對稱合成，使用光學活性試 映里播札±± "Ισ成，或經由以不對稱轉換使一對 、、物轉化成另-對映異構物而合成。 127788.doc •35- 200840567 當式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)之化合物 含有一個以上之對掌中心時，其可以非對映異構物形式存 在。非對映異構化合物可以熟悉本技藝者已知之方法分 離，例如層析或結晶，且個別之對映異構物可如上述般分 離。本發明包含式（I)、（la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物之各非對映異構物及其混合物。 某些式（I)、（la)、（II)、(III)、（IV)、（IVa)或（IVb)之化合 物可以不同之互變體形式或不同之幾何異構物存在，且本 發明包含式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)化合 物各互變體及/或幾何異構物及其混合物。 某些式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)之化合 物可以可分離之不同安定構造形式存在。由於不對稱單鍵 之受限制旋轉，例如因為立體阻礙或環張力造成之扭曲不 對稱使得分離不同構形成為可行。本發明包含式（1)、 (la)、（II)、（III)、（IV)、（IVa)或（IVb)之化合物之各構形異 構物及其混合物。 某些式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)之化合 物可以兩性離子形式存在且本發明包含式（I)、（la)、（II)、 (III)、（IV)、（IVa)或（IVb)化合物之各兩性離子形式及其混 合物。 至於本文所用名詞”前藥”係指可在體内藉由某些生理化 學過程轉化成母體藥物之藥劑（例如，需要在生理pH時之 前藥轉化成所需之藥物形式）。因為在某些情況下前藥比 母體藥物更容易投藥因此經常被使用。其可能可藉由例如 127788.doc -36- 200840567 口服投藥而為& & π 在醫藥組人“ σ用’但母體藥物則不然。前藥亦可能 ^ 具有優於母體藥物之改善溶解度。前藥之 二’二不限)將為本發明之化合物’其中該化合物係以酯 2投樂以助於通過其中水溶解度並沒有利之細胞膜， 但接者在水溶絰_女 合解度有利之細胞内時會經代謝性水解成 酸。 前藥具有許多有用性質。例如，前藥之水溶性可能比最 、之藥物更好’因此有助於藥物之靜脈内投藥。前藥亦可 能具有比最終藥物更高程度之口服生物可利用性。投藥 後，该剛藥會酵素性或化學性斷裂以利將最終之藥物輸送 至血液或組織中。The amount of the (Ic) compound or a combination of two or more such compounds. The therapeutically effective amount can also be a prophylactically effective amount. The amount effective for treatment will depend on the size and sex of the patient, the symptoms to be treated, the severity of the symptoms, and the results of the observations for the intended condition. The therapeutically effective amount can be determined by methods known to those skilled in the art. Physiologically acceptable salt refers to the physiological potency and properties of the free base, and the organic acid is mixed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or with an organic acid such as acid H. , smoldering sulfonic acid, sulphuric acid, p-toluene, citric acid, fumaric acid, maleic acid, carboxylic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (such as (ten) or tartaric acid or An amine acid (for example, a (+) or (a) amino acid or a mixture thereof) is obtained by a kite reaction. The salts may have an acidic substituent by a method known to those skilled in the art. Certain compounds of formula (1), (4), (11), (10), (IV), (Va) or (ivb) may be present as salts with pharmaceutically acceptable salts. The present invention encompasses such salts. Examples of such salts Sodium salts, potassium salts, persalts and arginine salts are included. These salts can be prepared by methods known to those skilled in the art 127788.doc -34. 200840567. Certain formulas (I), (ia), The compound of (II), (III), (IV), (IVa) or (IVb) and a salt thereof may exist in one or more crystalline forms, and The invention comprises the crystalline form and mixtures thereof. Certain compounds of formula (1), (Ia), (11), (ΙΠ), (IV), (IVa) or (IVb) and salts thereof may also be solvated, for example The form of the hydrate is present, and the present invention comprises the solvate and mixtures thereof. Certain compounds of formula (I), (la), (II), (111), (IV), (IVa) or (IVb) may = have - or more than the center of the palm, and exist in different optically active forms i When the compound of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) 3 There is a central, palm center, then the compound is in the form of two enantiomeric forms: and the invention comprises both enantiomers and mixtures of enantiomers such as antiseptic. Isomers may be formed by methods known to those skilled in the art, for example, by formation of diastereomeric salts which may be separated by, for example, crystallization; formation by, for example, crystallization, gas-liquid or liquid chromatography Separation of a non-imiding derivative or complex; selective reaction of an enantiomer with an enantiomerically specific reagent, eg, enzymatic acetification Or in the palmar environment, for example, in the palm of the hand and the dry support material, for example, with a combination of palmarity = body oxygen cut or in the presence of a palm solvent, by gas - liquid or: It should be understood that when the desired enantiomer is converted to a chemical entity by one of the above separation procedures, another step can be used to liberate the desired pair of reagents: the base ruthenium can be asymmetrically synthesized. , using optically active assays to broadcast ±± "Ισ成, or by asymmetrically converting a pair of substances into another-enantiomer. 127788.doc •35- 200840567 When the compound of I), (la), (II), (III), (IV), (IVa) or (IVb) contains more than one palm center, it may exist as a diastereomer. Diastereomeric compounds can be separated by methods known to those skilled in the art, such as chromatography or crystallization, and the individual enantiomers can be separated as described above. The present invention comprises each of the diastereomers of the compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) and mixtures thereof. Certain compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may exist in different tautomeric forms or different geometric isomers, and The invention comprises the tautomers and/or geometric isomers of the compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) and mixtures thereof. Certain compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may exist in different stable structural forms which are separable. Due to the restricted rotation of the asymmetric single bond, for example, the distortion is not symmetric due to steric hindrance or ring tension, making it possible to separate the different configurations. The present invention encompasses various conformational isomers of the compounds of formula (1), (la), (II), (III), (IV), (IVa) or (IVb) and mixtures thereof. Certain compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may exist in zwitterionic form and the invention comprises formula (I), (la), Each zwitterionic form of a compound of (II), (III), (IV), (IVa) or (IVb) and mixtures thereof. As used herein, the term "prodrug" refers to an agent that can be converted to a parent drug by certain physiological processes in the body (e.g., a prodrug that is required to be converted to the desired drug form at physiological pH). Because prodrugs are easier to administer than parent drugs in some cases, they are often used. It may be administered orally by, for example, 127788.doc -36-200840567 for && π in the medical group "snap" but not the parent drug. The prodrug may also have improved solubility over the parent drug. The second drug of the prodrug is not limited to the compound of the present invention, wherein the compound is esterified with the ester 2 to help the cell membrane which is not soluble in water solubility, but the solution is favorable in water dissolution. Metabolite hydrolysis into acid in cells. Prodrugs have many useful properties. For example, prodrugs may be more water soluble than most drugs, thus contributing to the intravenous administration of drugs. Prodrugs may also have a ratio The final drug has a higher degree of oral bioavailability. After administration, the drug will be enzymatically or chemically disrupted to facilitate delivery of the final drug to the blood or tissue.

斷裂後釋出相對應之游離酸及本發明化合物之該可水解 酯形成殘基之實例包含（但不限於）羧酸取代基（例如， -(CH2)C(0)0H或含有羧酸之基團），其中游離氫係經（Ci_ C4)烷基、（cvcy烷醯基氧基甲基、（C^C9)!-(烷醯基氧 基）乙基、具有5至10個碳原子之丨_甲基(烷醯基氧基）_乙 基、具有3至6個碳原子之烷氧基羰基氧基甲基、具有4至7 個碳原子之1-(烷氧基羰基氧基）乙基、具有5至8個碳原子 之1_甲基-1-(烧氧基魏基氧基）乙基、具有3至9個碳原子之 N-(烷氧基羰基）胺基甲基、具有4至10個碳原子之l(n_(烧 氧魏基）胺基）乙基、3-酞醢基、4-巴豆隨内g旨基 (crotonolactonyl)、γ-丁内酯-4-基、二-N’N^CVCJ燒基胺 基（cvc：3)烷基（如β-二曱胺基乙基）、胺甲醯基_(Cl-C2)烧 基、N，N-二（CVC2)-烷基胺曱醯基-(CVC2)烷基及哌咬基_ 127788.doc -37- 200840567 、吼嘻啶基-或嗎啉基（CVC3)烷基。 其他列舉之前藥釋出式⑴、（Ia)、（„)、（m)、（lv)、 (IVa)或（IVb)之醇，其中羥基取代基（例如…含有羥基）之氫 係經下列基置換：（Cl-C6)烷醯基氧基甲基、Examples of the residue which forms the corresponding free acid and the hydrolyzable ester of the compound of the present invention after cleavage include, but are not limited to, a carboxylic acid substituent (for example, -(CH2)C(0)0H or a carboxylic acid-containing compound. a group) wherein the free hydrogen is via (Ci_C4)alkyl, (cvcyalkylmercaptooxymethyl, (C^C9)!-(alkylhydrazino)ethyl, having 5 to 10 carbon atoms丨-methyl(alkylhydrazineoxy)-ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy) having 4 to 7 carbon atoms Ethyl, 1-methyl-1-(alkoxy-Wikiyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)amino group having 3 to 9 carbon atoms a l, (n-(anthracenyl)amino)ethyl, 3-indolyl, 4-croton, crotonolactonyl, γ-butyrolactone-4 having 4 to 10 carbon atoms -yl, bis-N'N^CVCJ alkylamino (cvc:3) alkyl (such as β-diamidinoethyl), amine carbaryl-(Cl-C2) alkyl, N, N- Di(CVC2)-alkylamine mercapto-(CVC2)alkyl and piperidinyl _ 127788.doc -37- 200840567 , acridinyl- or morpholinyl (CVC3) alkane Other alcohols of the formula (1), (Ia), („), (m), (lv), (IVa) or (IVb), wherein the hydrogen substituent of the hydroxy substituent (for example, containing a hydroxyl group) Substituted by: (Cl-C6) alkanoyloxymethyl,

醯基氧基）乙基、1-曱基烷醯基氧基）乙基、（Ci_ CO烷氧基羰基氧基甲基、N_(Ci_C0)烷氧基羰基胺基-甲 基、琥珀醯基、（CVC6)烷醯基、α_胺基（Ci_C4)烷醯基、芳 基醯基及α-胺基醯基，或心胺基醯基-心胺基醯基（其中該 心胺基醯基基團獨立為蛋白質中發現之任一天然l_胺基 酸）、P(o)(〇h)2、-P(0)(0(CVC6)院基）2 或糖基（因碳水二 合物之半縮醛之羥基脫離形成之殘基）。 本文所用之名詞，，雜環”或，，雜環基"包含非芳族環系統， 包含（但不限於）單環、雙環及三環，其可為完全飽和或可 含有-或多個不飽和單元(為避免質美是，不飽和程度不會 f生：族環系統)，且具有3至12個包含至少-個雜原子如 氮、氧或硫之原子。就舉例目的而言，在*視為限制本發 明範圍下’下列為雜環實例：叮庚因、π丫丁啶基 基、側氧基㈣基、縣基料録、料基、錢基、 吡咯啶基、喹寧啶(quinicludinyl)、硫嗎啉基、四氫吡喃 基及四氫呋喃基。 本文所用之名詞”雜芳基"包含芳族環系统，包含“曰不 限於）單環、雙環及三環㈣，且具有3至12個包含至少一 個雜原子如氮、氧或硫之原子。就舉例目的而言(不應視 為限制本發明之範圍）為：氮雜十朵基、苯并（㈣吩基、 127788.doc -38 - 200840567 苯并咪唑基、苯并呋喃基、苯并咩唑基、苯并噻唑基、苯 并售二嗤基、苯并三吐基、苯并崎二峻基、吱喃基、味嗤 基、味嗤并TI比U定基、σ引u朵基、,σ朵琳基、叫j ϋ坐基、異TI引u朵 琳基、異4 σ坐基、異嗟σ坐基、異唾琳基、p号二嗤基、4 σ坐 基、τι票呤基、υ比η南基、σ比嗓基、υ比σ坐基、σ比σ定基、tr密σ定 基、°比嘻基、°比嘻并[2,3-(1]嘴咬基、°比嗤并[3,4-(1]^1密淀 基、喧琳基、喧唾琳基、三嗤基、嗟嗤基、ϋ塞吩基、四氫 。引°朵基、四17坐基、17塞二σ坐基、σ塞吩基、硫嗎琳基、三嗤基 或托品烧基（tropanyl)。 當使用名詞”經取代之雜環π(或雜環基）或”經取代之雜芳 基π或”經取代之芳基”時，意指雜環、雜芳基或芳基經一 或多個取代基取代，該取代可由熟悉本技藝者執行且產生 為鞘氨醇受體族之激動劑或拮抗劑之分子。就舉例目的而 言（但不應視為限制本發明之範圍），本發明雜環、雜芳基 或芳基之較佳取代基各獨立選自由下列組成之視情況取代 之基：稀基、烧氧基、烧氧基烧氧基、烧氧基烧基、烧氧 基幾基、烧氧基幾基雜環烧氧基、烧基、烧基胺基、烧基 羰基、烷基酯、烷基-ΝΗ-烷基、-烷基-ΝΗ-環烷基、烷基 -O-C(O)-、烷基-雜環基、-烷基-環烷基、烷基-腈、炔 基、醯胺基、胺基、胺基烷基、胺基羰基、甲腈、羰基烷 氧基、羧醯胺基、CF3、CN、-C(0)OH、-C(0)H、-C(0)-C(CH3)3、 -OH、-c(o)o-烷基、-C(0)0-環烷基、-c(o)o-雜環基、 -c(o)o-烷基芳基、-c(o)-烷基、-c(o)-環烷基、-c(o)-雜 環基、環烷基、二烷基胺基烷氧基、二烷基胺基羰基烷氧 127788.doc -39- 200840567 基、二烷基胺基羰基、鹵素、雜環基、雜環烷基、雜環基 氧基、經基、羥基烧基、硝基、OCF3、側氧基、-〇-烧 基、·〇-雜芳基、·0·雜環基、-S02CH3、-S02NH2、 -S〇2NH -烧基、-S〇2N(烧基）2、四嗤基、嗟吩基烧氧基、 三氟甲基羰基胺基、三氟甲基石黃醯胺基、雜環基烧氧基、 雜環基-S(0)p、環烧基-S(0)p、烧基-S-、雜環基-S、雜環 烧基、環烧基烧基、雜環硫基、環烧基硫基、-Z105_ C(〇)N(R)2 . -Z105.N(R).C(O)-Z200 > -Z!05-N(R)-S(O)2- _ z·、-Z105-N(R)-C(O)-N(R)-Z2(>()、-N(R)、ΜΗ)-烷基、 -N(H)-環烷基、-C(0)R、-N(R)-C(0)0R、OR-C(O)-雜環 基-OR、Re及 _CH2ORc ; 其中P為0、1或2 ; 其中每次出現之Rc係獨立為鹵素、視情況取代之烷基、 視情況取代之芳基、_(Ci-c6)-NRdRe、_E-(CH2)r NRdRe、-E-(CH2)t-〇-烧基、_E_(CH2)rS_ 烧基或 i (CH2)t-〇H ； _ 其中t為約1至約6之整數； 每-人出現之Z1G5係獨立為共價鍵、烷基、烯基或炔基，·且 每次出現之z200係獨立選自視情況取代之選自由下列組 成群組之基.烷基、烯基、炔基、苯基、烷基_苯基、 晞基-苯基或炔基_苯基； :、鍵0 s、S(〇)、S(〇)2 或 NRf，其中 RA Η 或 烷基，且化及心獨立為Η、烷基、烷醯基或S〇2-烷基； 或Rd、Re與其所附接之氮原子一起形成五_或六·員雜壤 127788.doc 200840567 系環。 至約八個碳原子之 較佳之雜環烷基為 本文所用之，•雜環炫基”為藉由 脂族基與化合物鍵聯之雜環基。例如， 嗎啉基甲基。 全:二:族基”或符號如"(cvc8)”包含完 飽和h有-或多個不餘和單元之直鏈或分支烴，且因Mercaptooxy)ethyl, 1-decylalkyl decyloxy)ethyl, (Ci_CO alkoxycarbonyloxymethyl, N_(Ci_C0) alkoxycarbonylamino-methyl, amber fluorenyl , (CVC6) alkyl fluorenyl, α-amino (Ci_C4) alkyl fluorenyl, aryl fluorenyl and α-amino fluorenyl, or cardinyl fluorenyl-cardamine fluorenyl (wherein the cardinyl hydrazide) The radical group is independently any of the natural l-amino acids found in the protein), P(o)(〇h)2, -P(0)(0(CVC6)), or glycosyl (due to carbon dioxide) The hydroxyl group of the hemiacetal of the compound is detached from the residue formed.) The term "heterocyclic ring" or "heterocyclyl" as used herein includes a non-aromatic ring system including, but not limited to, monocyclic, bicyclic, and a tricyclic ring which may be fully saturated or may contain - or more than one unsaturated unit (to avoid mass, the degree of unsaturation does not occur: a family ring system), and have 3 to 12 containing at least one hetero atom An atom such as nitrogen, oxygen or sulfur. For purposes of example, * is considered to limit the scope of the invention 'The following are examples of heterocycles: azepine, π-azetidinyl, pendant oxy (tetra), county base , base, money base, pyrrole Acridine, quinolidine, thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl. The term "heteroaryl" as used herein, includes an aromatic ring system, including "not limited to" monocyclic, bicyclic And tricyclic (d), and having from 3 to 12 atoms containing at least one hetero atom such as nitrogen, oxygen or sulfur. For illustrative purposes (not to be construed as limiting the scope of the invention): aza-decyl, benzene And ((4) phenyl, 127788.doc -38 - 200840567 benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzofluorenyl, benzotriazole, benzoxaki Dijunji, 吱 基 、, miso base, miso and TI than U base, σ 引 u, σ 朵 琳 琳, j j ϋ sit, different TI 引 u 琳 琳, different 4 σ sit Basis, isoindole sigma, iso-saltyl, p-diyl, 4 σ, τ, 呤, υ, σ, σ, σ, υ, σ, σ, σ , tr dense σ fixed base, ° 嘻 嘻 base, ° 嘻 嘻 [2,3-(1] mouth bite base, ° ratio 嗤[3,4-(1]^1 densely based, 喧琳基,喧Salicyl, triterpene, fluorenyl, thiophene, tetrahydrogen.朵基,四17坐基,17塞二σ坐基, σ塞基基, thiophenanyl, triterpene or tropanyl. When using the noun "substituted heterocyclic π (or hetero "Cycloalkyl" or "substituted heteroaryl" or "substituted aryl" means that the heterocyclic, heteroaryl or aryl is substituted by one or more substituents which may be carried out by those skilled in the art. And a molecule which is an agonist or antagonist of the sphingosine receptor family. For purposes of illustration (but should not be construed as limiting the scope of the invention), preferred heterocyclic, heteroaryl or aryl groups of the invention are preferred. The substituents are each independently selected from the group consisting of the following substituents: a dilute group, an alkoxy group, an alkoxy group, an alkoxy group, an alkoxy group, an alkoxy group, a heterocyclic ring. Base, alkyl, alkyl amine, alkyl carbonyl, alkyl ester, alkyl-hydrazine-alkyl, -alkyl-hydrazine-cycloalkyl, alkyl-OC(O)-, alkyl-heterocycle , -alkyl-cycloalkyl, alkyl-nitrile, alkynyl, decylamino, amine, aminoalkyl, aminocarbonyl, carbonitrile, carbonyl alkoxy, carboxy oxime, CF3, CN , -C(0)OH, -C(0)H, - C(0)-C(CH3)3, -OH, -c(o)o-alkyl, -C(0)0-cycloalkyl, -c(o)o-heterocyclyl, -c(o O-alkylaryl, -c(o)-alkyl, -c(o)-cycloalkyl, -c(o)-heterocyclyl, cycloalkyl, dialkylaminoalkoxy, Dialkylaminocarbonyl alkoxy 127788.doc -39- 200840567 base, dialkylaminocarbonyl, halogen, heterocyclic, heterocycloalkyl, heterocyclyloxy, thiol, hydroxyalkyl, nitro , OCF3, pendant oxy, fluorene-alkyl, hydrazine-heteroaryl, ·0.heterocyclyl, -S02CH3, -S02NH2, -S〇2NH-alkyl, -S〇2N (alkyl) 2 , tetradecyl, porphinyloxy, trifluoromethylcarbonylamino, trifluoromethyl sulphate, heterocyclic alkoxy, heterocyclyl-S(0)p, cycloalkyl -S(0)p, alkyl-S-, heterocyclyl-S, heterocycloalkyl, cycloalkyl, heterocyclic thio, cycloalkylthio, -Z105_C(〇)N(R ) 2 - Z105.N(R).C(O)-Z200 > -Z!05-N(R)-S(O)2- _ z·, -Z105-N(R)-C(O )-N(R)-Z2(>(), -N(R), ΜΗ)-alkyl, -N(H)-cycloalkyl, -C(0)R, -N(R)-C (0)0R, OR-C(O)-heterocyclyl-OR, Re and _CH2ORc; wherein P is 0, 1 or 2; wherein each occurrence of Rc is independent Halogen, optionally substituted alkyl, optionally substituted aryl, _(Ci-c6)-NRdRe, _E-(CH2)r NRdRe, -E-(CH2)t-〇-alkyl, _E_(CH2 rS_alkyl or i(CH2)t-〇H; _ where t is an integer from about 1 to about 6; each ZZG5 is independently a covalent bond, an alkyl group, an alkenyl group or an alkynyl group, and Each occurrence of z200 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, phenyl, alkyl-phenyl, decyl-phenyl or alkynyl-benzene. a group; :, a bond 0 s, S (〇), S(〇) 2 or NRf, wherein RA Η or an alkyl group, and the radical and the heart are independently oxime, alkyl, alkanoyl or S〇2-alkyl; Or Rd, Re together with the nitrogen atom attached thereto to form a five- or six-member mixed soil 127788.doc 200840567 tether. A preferred heterocycloalkyl group to about eight carbon atoms is used herein, and a heterocyclic group is a heterocyclic group bonded to a compound by an aliphatic group. For example, morpholinylmethyl. "family base" or a symbol such as "quote (cvc8)" contains a saturated or h- or more than a straight or branched hydrocarbon of the unit, and

此：含：基、稀基、块基、及包括單、雙及三鍵之混合物 之、。备該基為C。時’意指該基團不存在或換 鍵。至於本文所f意W且包含完全飽和;直 鏈或分支之烴。較佳之烷基為甲I、乙基、丙基、丁基、 、己基及其異構基。至於本文所用之"烯基，及”炔基" d曰2 c8且包含含有一或多個不飽和單元(對烯基為一或 夕個雙鍵’且對炔基為一或多個三鍵)之直鏈或分支烴。 至於本文所用之芳族基（或芳基）包含芳族碳環系環系統 (例'，苯基及環戊二烯基)及稠合之多環系芳族環系糊 如，萘基、聯苯基及1，2,3,4-四氫萘基）。 至於本文所用之環烧基意指完全飽和或具有—或多個不 T和鍵但非相當於芳族基之CrC〗2單環或多環（例如，雙 %、三環等）烴。環烷基之較佳實例為環丙基、環丁基、 %戊基、環戊烯基、環己基及環己烯基。 至於本文所用之許多基團或取代基被稱為，，經取代，，或 ”視情況經取代”。當基團以此等名詞之一修飾時，除非另 有說明，否則代表熟悉本技藝者已知之可取代之基團任一 部份均可經取代，且包含一或多個取代基，其中若超過一 127788.doc -41 - 200840567 個取代基，則各取代基係獨立選擇。此意指針對取代為本 技藝中所習知及/或本揭示所教示。就舉例目的而言（但不 應視為限制本發明之範圍），取代基之某些實例為：埽 基、烷氧基（本身可經取代，如-0-C丨-CV烷基-OR、-Ο-Cl-cv烷基-n(r)2及ocf3)、烷氧基烷氧基、烷氧基羰基、烷 氧基羰基哌啶基-烷氧基、烷基（本身亦可經取代，如_Ci_ c6-烷基 _〇R、-Ci-CV烷基-N(R)2、COOH及-CF3)、烷基胺 基、烧基幾基、烧基酯、院基腈、烧基續醯基、胺基、胺 • 基烧氧基、CF3、COH、COOH、CN、環烷基、二烷基胺 基、一院基胺基烧氧基、二烧基胺基幾基、二燒基胺基魏 基烷氧基、二烷基胺基磺醯基、酯（_C(〇)-〇R，其中R為如 烧基、雜環烧基（可經取代）、雜環基等，其可經取代）、鹵 素或鹵基（F、C卜Br、I)、羥基、嗎啉基烷氧基、嗎啉基 烧基、-NH-CVCV烷基-COOH、硝基、側氧基、〇Cf3、 S(〇)2CH3、S(0)2CF3及磺醯基、N-烷基胺基或n，N-二烷基 胺碁（其中烷基亦可經取代）。 ® 使用方法 本發明提供通式⑴、（la)、（„)、（III)、（IV)、(IVa)或 (IVb)之化合物，該等化合物可有效作為G蛋白質_偶合之 S1P受體族之拮抗劑或激動劑。此等化合物可降低卩及心 淋巴細胞循環及滲透數而獲得有利之免疫壓抑作用。 本發明亦提供在S1P受體族中呈現活性之化合物。 本發明相關態樣係提供-種於罹患有其中調控sip活性 具有效益之疾病之人類標的中調控slp族受體之方法，該 127788.doc -42- 200840567 方法包括對該人類標的投與式（i)、（Ia)、（π)、（Ιπ>、 (IV)、（iva^(IVb)之化合物，使得於人類標的中調控sip 活性可被制約且達到治療。 本I月另一相關癌樣係提供一種調控勒氨醇1 _碟酸酷受 體1活性之方法，該方法包括使細胞與一或多種式（I)、 (la)、（II)、（III)、（IV)、（IVa)或（Ivb)之化合物接觸。This includes: a base, a dilute base, a block base, and a mixture comprising single, double and triple bonds. The base is prepared as C. Time ' means that the group does not exist or change key. As used herein, it is intended to include fully saturated; straight or branched hydrocarbons. Preferred alkyl groups are methyl I, ethyl, propyl, butyl, hexyl and isomers thereof. As used herein, "alkenyl," and "alkynyl" " d曰2 c8 and encompasses one or more units of unsaturation (one or one double bond for alkenyl group) and one or more a linear or branched hydrocarbon of a triple bond. As used herein, an aromatic group (or aryl group) includes an aromatic carbocyclic ring system (eg, phenyl and cyclopentadienyl) and a fused polycyclic ring system. An aromatic ring system paste such as naphthyl, biphenyl and 1,2,3,4-tetrahydronaphthyl). As used herein, a cycloalkyl group means fully saturated or has - or more than T and a bond but Non-equivalent to an aromatic group of CrC 2 monocyclic or polycyclic (eg, bis-, tricyclic, etc.) hydrocarbon. Preferred examples of cycloalkyl are cyclopropyl, cyclobutyl, % pentyl, cyclopentene a group, a cyclohexyl group, and a cyclohexenyl group. As used herein, a plurality of groups or substituents are referred to, substituted, or "optionally substituted." When a group is modified by one of the terms, unless Unless otherwise stated, any moiety that is representative of a substitutable group known to those skilled in the art may be substituted and include one or more substituents, wherein if more than one 127788.doc-41 - In the case of the above-mentioned substituents, the substituents are independently selected. It is intended to be a substitute for the teachings of the art and/or the teachings of the present disclosure. For purposes of example (but should not be construed as limiting the scope of the invention) Some examples of substituents are: fluorenyl, alkoxy (which may itself be substituted, such as -0-C丨-CV alkyl-OR, -Ο-Cl-cv alkyl-n(r)2, and ocf3 , alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl (which may itself be substituted, such as _Ci_c6-alkyl-〇R, -Ci-CV Alkyl-N(R)2, COOH and -CF3), alkylamino group, alkyl group, alkyl ester, fenyl nitrile, alkyl group, amine group, amine group, alkoxy group, CF3 , COH, COOH, CN, cycloalkyl, dialkylamino, a compound amine alkoxy group, dialkylamino group, dialkylamino group, alkyl alkoxy group, dialkylamino group A sulfonyl group, an ester (_C(〇)-〇R, wherein R is an alkyl group, a heterocyclic group (may be substituted), a heterocyclic group, etc., which may be substituted), a halogen or a halogen group (F, C) Br, I), hydroxy, morpholinoalkoxy, morpholinylalkyl, -NH-CVCV alkyl-COOH, nitrate Base, pendant oxy, 〇Cf3, S(〇)2CH3, S(0)2CF3 and sulfonyl, N-alkylamine or n,N-dialkylamine oxime (wherein the alkyl group may also be substituted) ® Method of Use The present invention provides compounds of the formula (1), (la), („), (III), (IV), (IVa) or (IVb) which are effective as G protein-coupled S1P An antagonist or agonist of the body. These compounds reduce the circulation and penetration of sputum and heart lymphocytes to obtain a favorable immunosuppressive effect. The invention also provides compounds which exhibit activity in the S1P receptor family. A related aspect of the present invention provides a method of modulating a slp family receptor in a human subject having a disease in which sip activity is beneficial, and the method of 127788.doc-42-200840567 includes administration of the human target ( i), (Ia), (π), (Ιπ>, (IV), (iva^(IVb) compounds, which regulate the sip activity in human targets and can be treated. Another related cancer of this month The sample provides a method of modulating the activity of Leminol 1 -disc 1 receptor, the method comprising reacting the cell with one or more of formula (I), (la), (II), (III), (IV), Contact with (IVa) or (Ivb) compounds.

式⑴、（la)、（II)、（III)、（IV)、（IVa)或（IVb)之化合物或 其鹽或含有治療有效量之該化合物之醫藥組合物可用於治 療選自包括下列群組之疾病·· CNS系統疾病、關節炎、風 濕^節炎、骨關節炎、幼年慢性關節炎、萊姆氏（Lyme) ，節人牛皮癖關節炎、反應性關節炎及敗血性關節炎、 :/病王身性紅斑狼瘡、克隆氏症、潰瘍性結腸 尺I灾丨生腸疾病、胰島素倚賴性糖尿病、甲狀腺炎、氣 2、過敏性疾病、牛皮癖、脂漏性皮脂炎硬皮症、移植對 =主之疾病、态官移植排斥（包含（但不限於）骨髓及實心器 吕之排斥）、®器官移植造成之急性或慢性免疫疾病、類 肉瘤、動脈粥狀硬化、瀰漫性血管内凝血、川崎病 (Kawasakls dlsease)、葛瑞夫兹症（仏靖，s disease)、腎病 ^、群^性疲勞症候群、偉格納（Wegener)肉芽腫、亨 Ife -修因連氏势 * ” ’丙（en〇ch_Schoenlein purpurea)、腎臟之 你支血管欠、慢性、、 茯古^ “生活化肝炎、葡萄膜炎、敗血性休克、毒性 休克症候群、敗血性症 f 、_、心、貝病、傳染性疾病、寄生 τ 免度不王症候群、急性橫質性脊髓炎、亨 丁頓舞踢症、帕金森 α餘海默氏症、中風、原發性膽 127788.doc -43- 200840567 汁鬱積性肝硬化、溶血性貧血、惡性腫瘤、心臟衰竭、心 肌梗基、阿迪氏症（Addison’s disease)、散發型運動失調症 (sporadic)、多内分泌腺不足第1型及多内分泌腺不足第π 型、施密特氏症候群（Schmidt’s syndrome)、成年人（急性） 呼吸窘迫徵候群、脫髮症、斑禿、血清陰性脊椎關節病 (seronegative arthopathy)、關節病、雷特氏（Reiter，s)症、 乾癣性關節病變、潰瘍性結腸炎關節炎、腸源性滑膜炎、 砂眼、鼠疫桿菌及沙門氏桿菌有關之關節炎、粥靡樣含脂 症/動脈粥樣硬化、異位性過敏、自體免異性水泡症、尋 常性天皰瘡、落葉型天皰瘡、天皰瘡、線性IgA症、自體 免疫性洛血性貧血、坎柏氏（C〇ombs)陽性溶血性貧血、後 天性惡性貧血、幼年惡性貧血、肌痛性腦炎/皇家游離性 疾病（Royal Free Disease)、慢性皮膚黏膜念珠菌症、巨細 胞動脈炎、原發性硬化性肝炎、隱原性自體免異性肝炎、 後天免疫不全症候群、後天免疫不全相關疾病、B型肝 k Ci肝k、正g變化之免疫不全（正常變化之丙種球蛋 白過低血症（hypogammaglobulinaemia))、擴張型心肌病 變、女性不孕症、卵巢衰竭、卵巢早衰、纖維性肺病、慢 性傷口癒合、隱原性致纖維性肺泡炎、發炎後之間質性肺 病、間質性肺炎、與間質性肺病有關之結締組織疾病、與 肺病有關之混合型結締組織疾病、與間質性肺病有關之全 身性硬化、與間質性肺病有關之風濕症關節炎、與肺病有 關之全身性紅斑狼瘡、與肺病有關之皮肌炎/多肌炎、與 肺病有關之休格林氏（Sjogren’s)症、與肺病有關之僵直性 127788.doc -44 - 200840567A compound of formula (1), (la), (II), (III), (IV), (IVa) or (IVb) or a salt thereof or a pharmaceutical composition comprising a therapeutically effective amount of the compound, which is useful for treatment, is selected from the group consisting of Group diseases · CNS system diseases, arthritis, rheumatism, osteoarthritis, juvenile chronic arthritis, Lyme, psoriatic arthritis, reactive arthritis and septic arthritis , / / disease of the disease, lupus erythematosus, Crohn's disease, ulcerative colonic disease I, intestinal diseases, insulin-dependent diabetes, thyroiditis, qi 2, allergic diseases, psoriasis, liposuction sebaceous crust Symptoms, transplantation versus disease, genital transplant rejection (including but not limited to bone marrow and solid sputum rejection), acute or chronic immune disease caused by organ transplantation, sarcoma, atherosclerosis, diffuse Intravascular coagulation, Kawasakis dlsease, Graves syndrome, s disease, kidney disease, group fatigue syndrome, Wegener granulomatosis, Henf Ife - Schneider's temperament* 'C (en〇ch_Schoenlein purpurea ), the kidney of your vascular owe, chronic, 茯古 ^ "living hepatitis, uveitis, septic shock, toxic shock syndrome, septicemia f, _, heart, shell disease, infectious diseases, parasitic τ Exemptive syndrome, acute transverse myelitis, Huntington's kick, Parkinson's alpha Heerlheimer's disease, stroke, primary biliary 127788.doc -43- 200840567 Septic cirrhosis, hemolytic Anemia, malignant tumor, heart failure, myocardial infarction, Addison's disease, sporadic, multiple endocrine gland deficiency type 1 and multiple endocrine gland deficiency type π, Schmidt's syndrome (Schmidt's syndrome), adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, dry joint disease, ulcer Arthritis, enterogenous synovitis, trachoma, plague and Salmonella-associated arthritis, porridge-like lipids/atherosclerosis, atopic allergy, autophagic immunity Bubble disease, pemphigus vulgaris, deciduous pemphigus, pemphigus, linear IgA, autoimmune hemophilic anemia, C〇ombs-positive hemolytic anemia, acquired pernicious anemia, juvenile malignancy Anemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency syndrome , acquired immunodeficiency related diseases, type B liver, k Ci liver k, positive g change immunodeficiency (normally changed hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, Premature ovarian failure, fibrotic lung disease, chronic wound healing, cryptogenic fibronectin, post-inflammatory interstitial lung disease, interstitial pneumonia, connective tissue disease associated with interstitial lung disease, mixed type with lung disease Connective tissue disease, systemic sclerosis associated with interstitial lung disease, rheumatoid arthritis associated with interstitial lung disease, systemic lupus erythematosus associated with lung disease, and Dermatomyositis/polymyositis associated with lung disease, Sjogren’s disease associated with lung disease, and stiffness associated with lung disease 127788.doc -44 - 200840567

:椎人a官擴散之肺病、與肺病有關之血黃素沉著症、 藥物引致之間質性肺病、放射纖維病、阻塞性細支氣管 炎、慢性嗜酸性粒細胞肺炎、淋巴性肺浸潤病變、後感染 之間質性肺病、痛風性關節炎、自體免疫性肝炎、第！型 自體免疫性肝炎（典型自體免疫性或狼瘡樣肝炎）、第2型自 體免㈣肝炎（HLKM抗體肝炎）、自體免疫介導之低血糖 症伴Ik黑色棘皮症之B型姨島素抗性、甲狀腺功能不 良:因器官移植造成之急性免疫性疾病、目器官移植造成 之I*又f生免疫1*生疾病、骨關節炎、原發性硬化性膽管炎、牛 皮癖1型、牛皮癖2型、特發性白血球減少症、自體免疫性 嘻中性白血球減少症、腎臟疾病N〇s、絲球體腎炎、腎臟 之微型血管炎、萊姆症（Lyme disease)、盤狀紅斑狼瘡、 男性原發性不育或_、精子自體免疫性疾病、多發性硬 化症（所有亞型）、父感性眼炎、結締性組織疾病之續發性 肺部高血壓、古德巴斯德症候群（G〇〇dpasture，s syndrome)、結節性多動脈炎之肺部損害、急性風濕熱、 風濕症脊椎炎、司提爾氏症（Still’s disease)、全身性硬皮 症、休格林氏徵候群（Sj0gren，s Syndr〇me)、高安氏症 (Takayasu’s disease)/動脈炎、自體免疫性血栓血球減少 症、特發性血栓血球減少症、自體免疫性甲狀腺疾病、甲 狀腺機能亢進、甲狀腺腫性自體免疫性甲狀腺低下症（橋 本氏症（Hashimoto s disease))、萎縮性自體免疫甲狀腺低 下症、原發性黏液性水腫、晶狀體葡萄膜炎、原發性血管 炎、白斑、急性肝臟疾病、慢性肝臟疾病、酒精性肝硬 127788.doc •45- 200840567 化、酒經引致之肝臟受損、膽汁鬱滯、特異體質性肝臟疾 病、藥物引致之肝炎、非酒精性脂肪性肝炎、過敏及氣 喘、B族鏈球菌（GBS)感染、精神疾病（例如憂鬱症及精神 分裂症）、Th2型及Thl型介導之疾病、急性及慢性疼痛（不 同幵> 式疼痛）、及癌症如肺癌、乳癌、胃癌、膀胱癌、結 腸癌、胰腺癌、卵巢癌、前列腺癌及直腸癌及造血異常之 惡性腫瘤（血癌及淋巴癌）、及造血異常之惡性腫瘤（血癌及 淋巴癌）、β脂蛋白缺乏症、手足紫斑症、急性及慢性寄生 或感染過程、急性白血病、急性淋巴細胞性白血病 (all)、急性脊髓白血病（AML)、急性或慢性細菌感染、 急性胰腺癌、急性腎臟衰竭、腺癌、呼吸道異位搏動、 AIDS癡呆併發症、酒經引致之肝炎、過敏性結膜炎、過 敏性接觸性皮膚炎、過敏性鼻炎、同體移植排斥、心^型 抗胰蛋白酶缺乏症、肌萎縮性脊椎側索硬化症、貧血、心 絞痛、前角細胞退化、抗cd3療法、抗磷脂症候群、抗受 體過敏性反應、主動脈及末梢動脈瘤、主動脈剝離、動脈 尚血壓、動脈粥樣硬化、動靜脈屢管、運動失調症、心房 纖維顫動（持續性或爆發性）、心房撲動、房室傳導阻滯、 B細胞淋巴癌、骨骼移植排斥、骨髓移植（ΒΜτ)排斥、束 支傳導阻滯、布肯氏淋巴癌（Burkiu，s lymph〇ma)、灼傷、 心律不整、心臟頓抑症候群、心臟腫瘤、心肌症、心肺旁 通之發炎反應、軟骨移植排斥、小腦皮質退化、小腦疾 病、紊亂或多源性心動過速、化學療法相關之疾病、絡酸 性骨髓性白血病（CML)、慢性酒精中毒、慢性發炎性疾 127788.doc • 46 - 200840567 病、悛性淋巴白血病（CLL)、慢性阻塞性肺部疾病 (COPD)、慢性水楊酸鹽中毒、結直腸癌、充血性心臟衰 竭、結膜炎、接觸性皮膚炎、肺心症、冠狀動脈疾病、庫 夏氏症（Cremzfeldt-Jakob disease)、培養陰性敗血症、囊 狀纖本化、細胞激素療法相關疾病、拳擊性癡呆症、脫髓 鞘症、出血性登革熱、皮膚炎、皮膚病症狀、糖尿病、糖 尿病、糖尿病血管硬化症、瀰漫性萊維（Lewy)小體病、擴 張性充血性心肌症、基底核之疾病、中年人之道氏 (Down’s)症候群、因阻斷CNS多巴胺受體之藥物引起之藥 物引致之動作失調、藥物過敏、濕疹、腦脊髓炎、心内膜 炎、内分泌異常、會厭炎、人類皰疹病毒感染、紅斑性肢 痛症、錐體外及小腦失調、家族嗜血細胞淋巴組織增生 症、女性胸腺植入排斥、肺得式運動失調症（Friedreich，s ataxia)、功能性末稍動脈失調症、黴菌敗血症、氣腫疽、 月、/貝瘍、腎小管性腎炎、任何器官或組織之移植排斥、格 蘭陰性敗血症、格蘭陽性敗血症、因細胞内組織造成之肉 芽腫、毛細胞白血病、哈雷登-史帕氏症（HaUerr〇rden_ Spatz Disease)、橋本氏甲狀腺炎、枯草熱、心臟移植排 斥、血色素沉著症、血液透析、溶血性尿毒症候群/溶解 血栓性血小板減少症、出血症、肝炎（A)、His束心律不 整、HIV感染/HIV神經性及病、何杰金氏症（H〇(Jgkinfs disease)、過動症、過敏性反應、過敏性肺炎、高血壓、 運動不足症、下視丘-腦下垂體_腎上線軸評估、特發性阿 迪森氏（Addison’s)症、特發性肺部纖維化、抗體介導之細 127788.doc -47- 200840567 胞毋虛弱嬰兒脊趙性肌萎縮症、主動脈發炎、A型 流行性感f、離子輻射暴露、虹膜結狀體㈣萄膜炎/視 神經炎、缺血·再灌注損傷、缺血性中風、幼年型風濕性 關即X、幼年型脊肌萎縮症、卡波西氏肉瘤(Kap〇si，s s—)、腎臟移植排彳、退伍軍人症、利什曼原蟲症、 癩病大皮貝㈣系統受損、脂水腫、肝臟移植排斥、 淋巴水腫、遽疾、亞#卜4、从m 士 ^ 、μ〖生淋巴瘤、惡性組織細胞增生症、异 性黑色素瘤、腦膜炎、腦膜炎球菌血症、代謝性/特： ':、偏頭痛 '線粒體多系統失調、混合型結締組織疾病、 單株免疫球蛋自增高症、多發性骨㈣m统退化 (Mencel Dejerine-Thomas Shi-Drager A Machado-J〇seph). 重症肌無力、細胞内禽結核桿菌、結核分枝桿菌、骨趙显 變症候群、心肌梗塞、心肌缺▲症、鼻咽癌、新生兒慢性 肺部疾病、腎炎、腎病變病、神經退化疾病、神經性⑶ 肌萎縮症、發燒性嗜中性白球低下症、非何杰金氏淋巴 瘤、不正常主動脈及其分支之阻塞、阻塞性動脈疾病、 〇kt3療法、睪丸/副睪丸炎、睪丸/輸精管復發程序、臟器 腫大、骨質疏鬆症、胰腺移植排彳、胰腺癌、腫瘤附屬症 =群/惡性腫瘤脂高血約症、甲狀旁腺移植排斥、骨盆發 太疾病、常年性鼻炎、心包疾病、末梢動末粥樣硬化疾 :、末梢血管疾病、腹膜炎、惡性貧血、卡氏肺囊蟲肺 九、肺炎、POEMS症候群（多發性神經病變、臟器腫大、 =分泌異f、單株免疫球蛋白増高、及皮膚改變症候 群）、灌注後症候群、泵浦後症候群、MI心切開後之症候 127788.doc -48- 200840567 群、子癇前期（preeclampsia)、漸發性核上麻痺、原發性肺 部高血壓、放射性療法、雷諾氏（Raynoud»s)現象及疾病、 雷諾氏症、雷蘇氏（Refsum’s)症、規律狹窄qRS心跳過 速、腎血管性高血壓、再灌注受損、限制型心肌症、内 瘤、硬皮症、老年性舞蹈症、萊維體型之老年痴呆症、血 〉月陰性脊椎關卽病、休克、錄刀型細胞貧血症、皮膚移植 排斥、皮膚改變症候群、小腸移植排斥、實心腫瘤、特異 性心律不整、脊椎性運動失調、脊髓小腦退化症、鏈球菌 肌炎、小腦構造受損、亞急性硬化泛腦炎、昏厥、心血管 系統之梅毒、全身性藥物過敏、全身性發炎反應症候群、 全身型幼年風濕性關節炎、T-細胞或FAB ALL、毛細血管 擴張、血栓閉塞性脈管炎、血小板過低症、毒性、移植、 腫瘤/出血、第III型過敏性反應、第IV型過敏、不穩定咽 喉炎、尿毒症、尿敗血症、蓴麻瘡、血管心臟疾病、靜脈 曲張、血管炎、靜脈疾病、靜脈栓塞、靜脈纖維化、病毒 及黴菌感染、病毒性腦炎/無菌性腦膜炎、與活體有關之 嗜血性症候群、Wernicke-Korsakoff症候群、威爾森 (Wilson’s)症、任何器官或組織之異種移植排斥、及包含 不當血管化之疾病例如糖尿病視網膜病變、早熟視網膜病 變、由於老人斑退化引起之脈絡膜血管新生形成及人類之 嬰兒金管瘤。另外’該等化合物可用於治療疾病如水腫、 腹水、溢出及滲出，包含例如黃斑部水腫、腦水腫、急性 肺部受損、成年人呼吸窘迫症候群（ARDS)，增生疾病如 再狹窄，纖維性疾病如肝硬化及動脈硬化，腎小球系膜細 127788.doc -49- 200840567 胞增生疾病如絲球體腎炎、糖尿病腎病變、惡性腎硬化、 栓塞性微血管病變症候群、及腎絲球病變、心肌血管新 生、冠狀動脈及小腦之側支循環、缺血性肢體血管新生、 缺血/再灌注受損、胃潰瘍螺旋菌（Helicobacter)相關疾 病、病毒引起之血管新生疾病、Cr〇w_Fukase症候群 (POEMS)、子癇前症、子宮不規則以、猫抓熱、皮膚發 紅、新生血官性青光眼及與糖尿病性視網膜病變、早產之 視網膜病變、老人斑退㈣中樞神經系統疾病有關之該等 視網膜病變。另外’該等化合物可用作抗實心腫瘤、惡性 腔瘤腹水、逢希伯-林道氏疾病（v〇n Hippel Undau disease' 造血性癌症及增生異常如甲狀腺增生（尤其是格霍夫氏症 (Grave’s disease))、及囊腫（如多囊性卵巢症候群之卵巢子 宮特性之高血管症（斯坦因_利文撒爾氏症候群（Skin· Leventhal syndrome)及多囊性腎臟疾病因為該等疾病需 要用於生長及/或轉移之血管細胞之增生）。 組合療法 本 t 月之式（I)、（la)、⑴）、（ln)、（Iv)、或化 口物可單獨使用或與其他治療劑組合使用以治療此等疾 病應了解本發明化合物可單獨使用4與其他藥劑如治療 J、口使用該其他藥劑係由熟知本技藝者就其所欲目的 、、擇例如’該其他藥劑可為本技藝認同之可用於治 療可由本發明化合物治療之疾病或病症之治療劑。該其他 藥J亦可為一使對於該治療組合物具有效益之藥劑，如影 響該組合物黏性之藥劑。 127788.doc •50- 200840567 進而應了解本發明所包含之組合為可用於其所欲用途之 該等組合。下述藥劑僅為舉例目的而非用以限制。為本發 明之一部分之此等組合可為本發明化合物與至少一種選自 下列之其他藥劑。若該組合為使所形成之組合物可執行其 所欲功能，則該組合亦包含一種以上之其他藥劑，例如兩 種或三種其他藥劑。 較佳之組合為非類固醇消炎藥，亦稱為NSAIDS，其包 含例如艾普吩（ibuprofen)之藥物。其他較佳之組合為皮質 籲 類固醇，包含去氫潑尼松（prednisolone);當與本發明之 S 1P受體激動劑或拮抗劑組合以治療病患時，藉由減弱所 需之類固醇劑量而可減低或甚至消除使用類固醇之悉知副 作用。可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa) 或（IVb)化合物組合而用於風濕性關節炎之治療劑的非限 制實例包含下列：細胞素抑制消炎藥（CSAIDs);為其他人 類細胞素或生長因子之抗體或拮抗劑，例如™?、！^、：^-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-12、 _ IL-15、IL-16、IL-21、IL-23、干擾素、£]^1八？-11、0河- CSF、FGF及PDGF。本發明之S/T激酶抑制劑可與細胞表 面分子之抗體如 CD2、CD3、CD4、CD8、CD25、CD28、 CD30、CD40、CD45、CD69、CD80 (B7.1)、CD86 (B7.2)、CD90、CTLA 或其配位體包含 CD154(gp 39 或 CD40L)組合。 治療劑之較佳組合可在自體免疫及隨後之發炎級聯中不 同位點干擾；較佳實例包含TNF拮抗劑，如嵌合、人類化 I27788.doc -51 - 200840567 或人類TNF抗體、D2E7(HUMIRAtm)(PCT專利公告號WO 97/29131)、CA2(REMICADEtm)、CDP 571 及可溶 p55 或 p75 TNF受體、其衍生物（p75TNFRlgG (ENBRELTM)或 p5 5TNFRl gG (Lenercept))以及 TNFa轉化酵素（TACE)抑制 劑；類似地IL-1抑制劑（介白素-1-轉化酵素抑制劑、IL-1RA等）基於相同理由而可能係有效的。其他較佳組合包含 介白素11。又其他較佳組合為可類似IL-1 8功能地作用、 倚賴其而作用或與其共同作用之自體免疫反應之其他主要 扮演者；尤佳者為IL-12拮抗劑，包含IL-12抗體或可溶IL-12受體、或IL-12結合蛋白質。IL-12及IL-18已顯示具有重 疊但不同之功能且與兩者之拮抗劑組合可能最有效。又其 他較佳組合為非耗竭性抗-CD4抑制劑。又其他較佳組合包 含共刺激路徑CD80(B7.1)或CD86 (B7.2)之激動劑，包含 抗體、可溶受體或拮抗性配位體。 本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)化 合物亦可與如下列之藥劑組合··敦甲σ集呤（methotrexate)、 6-MP、氮雜硫嗓吟石黃沙嗓（azathioprine sulphasalazine)、 馬沙嗪 （mesalazine)、 歐沙嗓氯啥 （olsalazine chloroquinine)/經基氯啥、青黴胺（pencillamine)、歐諾塞 馬特（aurothiomalate)(肌肉内及口服）、氮雜硫嘌吟、秋水 仙鹼（cochicine)、皮質類固醇（口服、吸入及局部注射）、 β-2腎上腺受體激動劑（沙丁胺醇（salbutamol)、特丁啉 (terbutaline)、沙莫特（salmeteral))、黃嘌吟類（茶鹼、胺茶 驗）、色甘酸鹽（cromoglycate)、耐多羅米（nedocromil)、酮 i27788.doc -52· 200840567: vertebral a patient's diffuse lung disease, hemorrhagic disease associated with lung disease, drug-induced interstitial lung disease, radiation fiber disease, obstructive bronchiolitis, chronic eosinophilic pneumonia, lymphatic lung infiltration lesions, after Infection between qualitative lung disease, gouty arthritis, autoimmune hepatitis, first! Autoimmune hepatitis (typical autoimmune or lupus-like hepatitis), type 2 autologous (4) hepatitis (HLKM antibody hepatitis), autoimmune-mediated hypoglycemia with Ik acanthosis type B Island resistance, thyroid dysfunction: acute immune diseases caused by organ transplantation, I* and f-immunity 1* diseases, osteoarthritis, primary sclerosing cholangitis, psoriasis Type, psoriasis type 2, idiopathic leukopenia, autoimmune sputum neutropenia, kidney disease N〇s, spheroid nephritis, microvascular vasculitis of the kidney, Lyme disease, plate Lupus erythematosus, male primary infertility or _, sperm autoimmune disease, multiple sclerosis (all subtypes), paternal ocular inflammation, connective tissue disease, continuous pulmonary hypertension, Goode P〇〇dpasture (s syndrome), pulmonary damage of nodular polyarteritis, acute rheumatic fever, rheumatic spondylitis, Still's disease, systemic scleroderma, rest Green's syndrome (Sj0gren, s Syndr〇me), Takayasu's disease/arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goiter autoimmune Hypothyroidism (Hashimoto s disease), atrophic autoimmune hypothyroidism, primary mucinous edema, lens uveitis, primary vasculitis, leukoplakia, acute liver disease, chronic liver Disease, alcoholic liver 127788.doc •45- 200840567 liver damage caused by alcohol, alcohol stagnation, idiopathic liver disease, drug-induced hepatitis, non-alcoholic steatohepatitis, allergies and asthma, B Streptococcus mutans (GBS) infection, mental illness (such as depression and schizophrenia), Th2 type and Th1 type mediated diseases, acute and chronic pain (different 幵 > pain), and cancer such as lung cancer, breast cancer, Gastric cancer, bladder cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, rectal cancer, and hematopoietic malignant tumors (blood cancer and lymphoma), and Abnormal malignancies (blood cancer and lymphoma), beta lipoprotein deficiency, chiropractic, acute and chronic parasitic or infection processes, acute leukemia, acute lymphocytic leukemia (all), acute myeloid leukemia (AML), acute or Chronic bacterial infection, acute pancreatic cancer, acute kidney failure, adenocarcinoma, respiratory ectopic beat, AIDS dementia complications, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection , heart type antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti-cd3 therapy, antiphospholipid syndrome, anti-receptor allergic reaction, aortic and peripheral aneurysms, Aortic dissection, arterial blood pressure, atherosclerosis, arteriovenous catheter, dyskinesia, atrial fibrillation (sustained or explosive), atrial flutter, atrioventricular block, B-cell lymphoma, bone graft Rejection, bone marrow transplantation (ΒΜτ) rejection, bundle branch block, Burkiu, s lymph〇ma, burn, heart Abnormality, cardiac stagnation syndrome, cardiac tumor, cardiomyopathy, inflammatory response of cardiopulmonary bypass, cartilage transplant rejection, cerebellar cortical degeneration, cerebellar disease, disorder or multi-source tachycardia, chemotherapy-related diseases, lytic acid bone marrow Leukemia (CML), chronic alcoholism, chronic inflammatory disease 127788.doc • 46 - 200840567 Disease, spastic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate poisoning, colorectal Cancer, congestive heart failure, conjunctivitis, contact dermatitis, pulmonary heart disease, coronary artery disease, Cremzfeldt-Jakob disease, culture-negative sepsis, cystic fibrosis, cytokine therapy-related diseases, boxing Dementia, demyelinating, hemorrhagic dengue, dermatitis, dermatological symptoms, diabetes, diabetes, diabetic vascular sclerosis, diffuse Lewy's small body disease, dilated congestive cardiomyopathy, basal ganglia Disease, middle-aged Down's syndrome, drug-induced dysregulation caused by drugs that block CNS dopamine receptors, drugs Allergies, eczema, encephalomyelitis, endocarditis, endocrine abnormalities, epiglottis, human herpesvirus infection, erythematous limb pain, extrapyramidal and cerebellar disorders, family hematopoietic lymphoproliferative, female thymus implantation Rejection, lunge-type movement disorder (Friedreich, s ataxia), functional terminal arterial dysfunction, mold sepsis, emphysema, monthly, / benign ulcer, renal tubular nephritis, transplant rejection of any organ or tissue, Blue-negative sepsis, glan-positive sepsis, granuloma due to intracellular tissue, hairy cell leukemia, HaUerr〇rden_Spatz Disease, Hashimoto's thyroiditis, hay fever, heart transplant rejection, hemoglobin Septicosis, hemodialysis, hemolytic uremic syndrome/dissolved thrombotic thrombocytopenia, hemorrhagic disease, hepatitis (A), His bundle arrhythmia, HIV infection/HIV neurological and disease, Hodgkin's disease (H〇 (Jgkinfs) Disease), hyperactivity, allergic reaction, hypersensitivity pneumonitis, hypertension, hypokinesia, hypothalamus - pituitary gland _ suprarenal axis assessment, idiopathic Adi Addison's disease, idiopathic pulmonary fibrosis, antibody-mediated fine 127788.doc -47- 200840567 毋 毋 婴儿 婴儿 脊 脊 性 性 、 、, aortic inflammation, type A epidemic f, ionizing radiation Exposure, iris knot (4) smear inflammation / optic neuritis, ischemia/reperfusion injury, ischemic stroke, juvenile rheumatic closure, X, juvenile spinal muscular atrophy, Kaposi's sarcoma (Kap〇si , ss-), kidney transplant sputum, veterans, leishmaniasis, rickets, pebbles (four) system damage, lipid edema, liver transplant rejection, lymphedema, dysentery, ya #卜4, from m ±, μ, lymphoma, malignant histiocytosis, heterosexual melanoma, meningitis, meningococcalemia, metabolic/special: ':, migraine' mitochondrial multisystemic disorders, mixed connective tissue disease, Single-immune immunoglobulin self-improvement, multiple bone (4) m system degeneration (Mencel Dejerine-Thomas Shi-Drager A Machado-J〇seph). Myasthenia gravis, intracellular Avian Mycobacterium tuberculosis, Mycobacterium tuberculosis, bone dysplasia Syndrome, myocardial infarction, myocardial insufficiency, Nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephropathy, neurodegenerative diseases, neuropathic (3) muscular dystrophy, fever neutropenia, non-Hodgkin's lymphoma, abnormal aorta and Branching obstruction, obstructive arterial disease, 〇kt3 therapy, sputum/paraplectic sputum, sputum/vas deferens recurrence procedure, organ enlargement, osteoporosis, pancreatic transplant sputum, pancreatic cancer, tumor dysfunction=group/malignant Tumor lipid hyperemia, parathyroid transplant rejection, pelvic effusion disease, perennial rhinitis, pericardial disease, peripheral atherosclerosis: peripheral vascular disease, peritonitis, pernicious anemia, Pneumocystis carinii lung Nine, pneumonia, POEMS syndrome (multiple neuropathy, organ enlargement, = secretory f, high immunoglobulin periosis, and skin modification syndrome), post-perfusion syndrome, post-pump syndrome, MI heart incision Symptoms 127788.doc -48- 200840567 Group, preeclampsia, progressive supranuclear palsy, primary pulmonary hypertension, radiation therapy, Raynoud's phenomenon and disease Raynaud's disease, Refsum's disease, regular stenosis qRS tachycardia, renal vascular hypertension, reperfusion injury, restrictive cardiomyopathy, endometrial, scleroderma, senile chorea, Levi's body type Alzheimer's disease, blood, monthly negative spinal cord disease, shock, knife-type cell anemia, skin graft rejection, skin modification syndrome, small bowel transplant rejection, solid tumor, specific arrhythmia, spinal dysregulation, spinal cerebellum Degenerative disease, streptococcal myositis, impaired cerebellar structure, subacute sclerosing encephalitis, fainting, syphilis of the cardiovascular system, systemic drug allergy, systemic inflammatory response syndrome, systemic juvenile rheumatoid arthritis, T-cell Or FAB ALL, telangiectasia, thromboangiitis obliterans, thrombocytopenia, toxicity, transplantation, tumor/bleeding, type III allergic reaction, type IV allergy, unstable pharyngitis, uremia, urinary sepsis , urticaria, vascular heart disease, varicose veins, vasculitis, venous disease, venous thrombosis, venous fibrosis, viral and fungal infections, viruses Encephalitis/aseptic meningitis, living-related haemophilia syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, and diseases including inappropriate vascularization such as diabetic retinopathy, Early maturity retinopathy, choroidal neovascularization due to age-related plaque degeneration and human infantile vascular tumor. In addition, these compounds can be used to treat diseases such as edema, ascites, spillage and exudation, including, for example, macular edema, cerebral edema, acute lung damage, adult respiratory distress syndrome (ARDS), proliferative diseases such as restenosis, fibrosis Diseases such as cirrhosis and arteriosclerosis, glomerular mesangial 127788.doc -49- 200840567 Cell proliferative diseases such as spheroid nephritis, diabetic nephropathy, malignant nephrosclerosis, embolic microangiopathy syndrome, and renal spheroid lesions, myocardium Angiogenesis, collateral circulation of the coronary arteries and cerebellum, ischemic limb angiogenesis, ischemia/reperfusion injury, Helicobacter-related diseases, viral-induced angiogenesis, Cr〇w_Fukase syndrome (POEMS) , preeclampsia, uterine irregularities, cats catching heat, skin redness, neonatal glaucoma and retinopathy associated with diabetic retinopathy, recurrent retinopathy of prematurity, and senile plaque (4) central nervous system diseases. In addition, these compounds can be used as anti-solid tumors, malignant tumors, ascites, and hemorrhagic cancer (v〇n Hippel Undau disease) and hyperplasia such as thyroid hyperplasia (especially Grave's disease)) and cysts (such as ovarian uterus characteristics of polycystic ovary syndrome) (Skin·Leventhal syndrome and polycystic kidney disease because these diseases need to be used Proliferation of vascular cells that grow and/or metastasize. Combination therapy The formula (I), (la), (1)), (ln), (Iv), or iridoin of this month can be used alone or in combination with other therapeutic agents. Used in combination to treat such diseases, it is understood that the compounds of the present invention can be used alone 4 and other agents such as treatment J. Oral administration of the other agents is well known to those skilled in the art for their intended purpose, for example, Therapeutic agents useful in the treatment of a disease or condition treatable by a compound of the invention may also be a pharmaceutical agent that is beneficial to the therapeutic composition, such as affecting the group The viscous agent. 127788.doc • 50- 200840567 It is further understood that the combinations encompassed by the present invention are such combinations that can be used for their intended use. The following agents are for illustrative purposes only and are not intended to be limiting. Such a combination may be a compound of the invention and at least one other agent selected from the group consisting of: If the combination is such that the resulting composition performs its intended function, the combination also includes more than one other agent, for example Two or three other pharmaceutical agents. A preferred combination is a non-steroidal anti-inflammatory drug, also known as NSAIDS, which comprises a drug such as ibuprofen. Other preferred combinations are corticosteroids, including prednisolone (prednisolone). When combined with the S1P receptor agonist or antagonist of the present invention to treat a patient, the known side effects of using the steroid can be reduced or even eliminated by attenuating the required steroid dose. Non-limiting examples of therapeutic agents for rheumatoid arthritis in combination of (I), (la), (II), (III), (IV), (IVa) or (IVb) compounds include the following Cytokine inhibitory anti-inflammatory drugs (CSAIDs); antibodies or antagonists of other human cytokines or growth factors, such as TM?, !^, :^-1, IL-2, IL-3, IL-4, IL-5 , IL-6, IL-7, IL-8, IL-12, _ IL-15, IL-16, IL-21, IL-23, interferon, £]^1 八-11, 0 river - CSF , FGF and PDGF. The S/T kinase inhibitor of the present invention can bind to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86. (B7.2), CD90, CTLA or its ligands comprise a combination of CD154 (gp 39 or CD40L). Preferred combinations of therapeutic agents can interfere with different sites in autoimmune and subsequent inflammatory cascades; preferred examples include TNF antagonists, such as chimeric, humanized I27788.doc-51 - 200840567 or human TNF antibodies, D2E7 (HUMIRAtm) (PCT Patent Publication No. WO 97/29131), CA2 (REMICADEtm), CDP 571 and soluble p55 or p75 TNF receptors, derivatives thereof (p75TNFRlgG (ENBRELTM) or p5 5TNFR1 gG (Lenercept)) and TNFa transformation An enzyme (TACE) inhibitor; similarly an IL-1 inhibitor (interleukin-1-transferase inhibitor, IL-1RA, etc.) may be effective for the same reason. Other preferred combinations include interleukin 11. Still other preferred combinations are other major players that act similarly to, act upon, or interact with IL-1 8; particularly preferred are IL-12 antagonists, comprising IL-12 antibodies Or soluble IL-12 receptor, or IL-12 binding protein. IL-12 and IL-18 have been shown to have overlapping but distinct functions and may be most effective in combination with antagonists of both. Still other preferred combinations are non-exhaustive anti-CD4 inhibitors. Still other preferred combinations comprise an agonist of the costimulatory pathway CD80 (B7.1) or CD86 (B7.2) comprising an antibody, a soluble receptor or an antagonistic ligand. The compound of the formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention may also be combined with a pharmaceutical agent such as the following: methotrexate , 6-MP, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine / chlorpyrifos, pencillamine, 诺诺塞Aurothiomalate (intramuscular and oral), azathioprine, colchicine, corticosteroid (oral, inhaled, and topical), beta-2 adrenoreceptor agonist (salbutamol, Terbutaline, salmeteral, xanthine (theophylline, amine tea), cromoglycate, nedocromil, ketone i27788.doc -52 · 200840567

替吩（ketotifen)、艾普托平（ipratropium)及歐托平 (oxitropium)、環孢素（cyclosporin)、FK506、雷帕黴素 (rapamycin)、馬替麥考分酯（mycophenolate mofetil)、來氟 米特（leflunomide)、NSAID，例如艾普吩、皮質類固醇如 去氫波尼松、填酸二S旨酶抑制劑、腺苷激動劑、抗jk栓 劑、補體抑制劑（complement inhibitors)、腎上腺劑、藉前 發炎細胞素干擾發訊之藥劑如TNF或IL-1 (如IRAK、NIK ; IKK、p3 8或MAP激酶抑制劑）、IL-Ιβ轉化酵素抑制劑、T-細胞發訊抑制劑如激酶抑制劑、金屬蛋白酶抑制劑、磺沙 唤（sulfasalazine)、6-氫硫基嘌呤、血管緊張素轉化酵素抑 制劑、可溶細胞素受體及其衍生物（如可溶p55或p75 TNF 受體及衍生物 p75 TNFRIgG(EnbrelTM 及 p55TNFRIgG (Lenercept))、sIL-lRI、sIL-lRII、sIL-6R)、消炎細胞素 (如 IL-4、IL-10、IL-11、IL-13 及 TGFP)、塞來考昔 (celecoxib)、葉酸、羥基氣喹硫酸鹽、羅氟考昔 (rofecoxib)、恩特納色（etanercept)、音氟脈（infliximab)、 納普森（naproxen)、瓦待考昔（valdecoxib)、石黃沙唤、甲基 去氫波尼松、美羅希肯（meloxicam)、甲基去氫波尼松乙酸 鹽、硫代蘋果酸金鈉、阿斯匹靈、乙醯替崔胺希諾酮 (triamcinolone acetonide)、丙氧吩萘磺酸鹽（propoxyphene napsylate)/apap、葉酸鹽、納普美酮（nabumetone)、二氯吩 納（diclofenac)、。比羅希肯（piroxicarn)、 艾妥多羅 (etodolac)、二氣吩鋼（(11〇1〇：{^113。3〇(1111111)、歐普口秦 (oxaprozin)、氧可酮（oxycodone)HCl、氫可體松 127788.doc -53- 200840567Ketofenfen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide Leflunomide, NSAID, such as Apoptin, corticosteroids such as deferxonone, acid-lowering enzyme inhibitors, adenosine agonists, anti-jk suppositories, complement inhibitors, adrenal agents, Agents that interfere with signaling by proinflammatory cytokines such as TNF or IL-1 (such as IRAK, NIK; IKK, p38 or MAP kinase inhibitors), IL-Ιβ-converting enzyme inhibitors, T-cell signaling inhibitors such as kinases Inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-hydroxythioguanidine, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (eg soluble p55 or p75 TNF receptors) And derivatives p75 TNFRIgG (EnbrelTM and p55TNFRIgG (Lenercept)), sIL-1RI, sIL-lRII, sIL-6R), anti-inflammatory cytokines (such as IL-4, IL-10, IL-11, IL-13 and TGFP) , celecoxib, folic acid, hydroxy quinoxaline, rofluzoxib ( Rofecoxib), etanercept, infliximab, naproxen, valdecoxib, scutellaria, methyl dehydroponenon, and meroxigen Meloxicam), methyl dehydroponben acetate, sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate / Apap, folate, nabumetone, diclofenac. Piroxicarn, etodolac, dioxent steel ((11〇1〇: {^113.3〇(1111111), oxaprozin, oxycodone) HCl, hydrogen cortisone 127788.doc -53- 200840567

(hydrocodone)酒石酸氫鹽/apap、二氯吩鈉/米舒普特 (misoprostol)、吩坦（fentanyl)、胺納奇拉（anakinra)、特莫 朵（tramadol)HCl、沙沙特（salsalate)、舒林達（sulindac)、 氰可巴明（cyanocobalamin)/fa/°比多嗓（pyridoxine)、捕熱息 痛（acetaminophen)、阿侖膦酸鈉（alendronate sodium)、去 氫波尼松、硫酸嗎啡、利多卡因鹽酸鹽、消炎痛 (indomethacin)、葡糖胺硫酸鹽 /可朵 ί丁（chondroitin)、阿米 替林（amitriptyline) HC1、石黃二嗪（sulfadiazine)、氧可酮 (oxycodone)HCl/捕熱息痛、歐羅普咬HC1米舒普特 (olopatadine HC1 misoprostol)、納普森納、歐美普峻 (omeprazole)、環填醢胺、利土脈（rituximab)、IL-1 TRAP、MRA、CTLA4-IG、IL-18 BP、抗-IL-12、抗-IL15、BIRB-796、SCIO-469、VX-702、AMG-548、VX-740、羅氟脈特（Roflumilast)、IC-485、CDC-801及馬舒潘 (Mesopram)。較佳組合包含氨曱嗓呤或來氟米特 (leflunomide)，且在中度或嚴重風濕性關節炎病例中，為 上述之環孢素及抗-TNF抗體。 可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療發炎性腸疾病之治療劑之非限 制性實例包含下列：布替耐德（budenoside);表皮生長因 子；皮質類固醇；環孢素、磺沙嗪；胺基水揚酸酯；6-氫 硫基嘌呤；氮雜硫嘌呤；美托尼達嗤（metronidazole);脂 氧酶抑制劑；美沙明（mesalamine);歐沙嗓（olsalazine); 貝沙奇（balsalazide);抗氧化劑；凝血崎烷抑制劑；IL-1受 127788.doc -54- 200840567 體拮抗劑；抗-IL-Ιβ單株抗體；抗-IL-6單株抗體；生長因 子；彈性酶抑制劑；吡啶基-咪唑化合物；對其他人類細 胞素或生長因子之抗體或拮抗劑，例如TNF、LT、IL-1、 IL-2 ^ IL-6 > IL-7 ^ IL-8 - IL-12 ^ IL-15 ^ IL-16 ^ EMAP-II、GM-CSF、FGF及 PDGF ;細胞表面分子如 CD2、CD3、 CD4 、 CD8 、 CD25 、 CD28 、 CD30 、 CD40 、 CD45 、 CD69、CD90或其配位體；氨曱喋呤；環孢素；FK506 ; 雷帕酶素；嗎替麥考紛酯（my cophenol ate mo fetil);雷氱脈 (leflunomide) ; NSAIDs，例如艾普吩；皮質類固醇如去氫 波尼松；磷酸二酯酶抑制劑；腺苷激動劑；抗凝血劑；補 體抑制劑；腎上腺劑；藉前發炎細胞素干擾發訊之藥劑如 TNF 或 IL-1(如 IRAK、NIK、IKK或 MAP激酶抑制劑）；IL-1 冷轉化酵素抑制劑；TNF α轉化酵素抑制劑；T-細胞發訊 抑制劑如激酶抑制劑；金屬蛋白酶抑制劑；磺沙嗪；氮雜 硫嘌呤；6-氫硫基嘌呤；血管緊張素轉化酵素抑制劑；可 溶細胞素受體及其衍生物（如可溶ρ55或p75 TNF受體、sIL-iRI 、 sIL-lRII 、 SIL-6R)及消炎 細胞素（如 IL-4 、 IL-10 、 IL-11、IL-13 及 TGF )。可與本發明之式（I)、（la)、(II)、 (III)、（IV)、（IVa)或（IVb)化合物組合用以治療克隆氏症之 治療劑之較佳實例包含下列：TNF拮抗劑例如抗-TNF抗 體、D2E7(PCT專利公告號 WO 97/29131 ; HUMIRAtm)、 CA2(REMICADE™) 、 CDP 571 、 TNF-Ig 架構物 (p75TNFRIgG (ENBRELtm)及p55TNFRIgG (LENERCEPTtm)) 抑制劑以及PDE4抑制劑。本發明之式（I)、（la)、（II)、 127788.doc -55- 200840567 (in)、(IV)、(IVa)或(Ivb)化合物可與皮質類固醇組合，例 如布替耐德（budenoside)及地塞米松（dexamethas〇ne);磺 沙嗪；5-胺基水楊酸；歐沙嗪；及干擾前發炎細胞素合成 或作用之藥劑如IL-1，例如IL-1 β轉畫酶抑制劑及比-丨以；(hydrocodone) hydrogen tartrate/apap, sodium dichlorophene/misopprostol, fentanyl, anakinra, tramadol HCl, salsalate, Sulindac, cyanocobalamin/fa/°pyridoxine, acetaminophen, alendronate sodium, deferxonone, sulphuric acid Morphine, lidocaine hydrochloride, indomethacin, chondroitin, amitriptyline HC1, sulfadiazine, oxycodone ( Oxycodone) HCl / acetaminophen, olpatadine HC1 misoprostol, aptsona, omeprazole, cyclopamine, rituximab, IL- 1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast ), IC-485, CDC-801 and Mesopram. A preferred combination comprises amidine or leflunomide, and in the case of moderate or severe rheumatoid arthritis, the above cyclosporine and anti-TNF antibodies. Non-limiting examples of therapeutic agents useful in the treatment of inflammatory bowel disease in combination with a compound of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) according to the invention Contains the following: budenoside; epidermal growth factor; corticosteroids; cyclosporine, sulfloxacin; aminosalicylate; 6-hydrosulfanyl hydrazine; azathiopurine; Metronidazole); lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; antioxidant; coagulation inhibitor; IL-1 127788.doc -54- 200840567 Antagonist; anti-IL-Ιβ monoclonal antibody; anti-IL-6 monoclonal antibody; growth factor; elastase inhibitor; pyridyl-imidazole compound; antibody or antagonist to other human cytokines or growth factors, for example TNF, LT, IL-1, IL-2 ^ IL-6 > IL-7 ^ IL-8 - IL-12 ^ IL-15 ^ IL-16 ^ EMAP-II, GM-CSF, FGF and PDGF; Surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; Aminoguanidine; Cyclosporine; FK506; Enzyme; my cophenol ate mo fetil; leflunomide; NSAIDs, such as eptophene; corticosteroids such as dehydroponentine; phosphodiesterase inhibitors; adenosine agonism Anticoagulant; complement inhibitor; adrenal agent; agents that interfere with signaling by proinflammatory cytokines such as TNF or IL-1 (eg IRAK, NIK, IKK or MAP kinase inhibitors); IL-1 cold transformase Inhibitor; TNFα-converting enzyme inhibitor; T-cell signaling inhibitor such as kinase inhibitor; metalloproteinase inhibitor; sulsarazine; azathiopurine; 6-hydroxythioguanidine; angiotensin-converting enzyme inhibitor Soluble cytokine receptors and their derivatives (such as soluble ρ55 or p75 TNF receptor, sIL-iRI, sIL-lRII, SIL-6R) and anti-inflammatory cytokines (such as IL-4, IL-10, IL-) 11, IL-13 and TGF). Preferred examples of therapeutic agents which can be combined with the compounds of the formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention for the treatment of Crohn's disease include the following : TNF antagonists such as anti-TNF antibody, D2E7 (PCT Patent Publication No. WO 97/29131; HUMIRAtm), CA2 (REMICADETM), CDP 571, TNF-Ig framework (p75TNFRIgG (ENBRELtm) and p55TNFRIgG (LENERCEPTtm)) inhibition And PDE4 inhibitors. Formula (I), (la), (II), 127788.doc -55- 200840567 (in), (IV), (IVa) or (Ivb) compounds of the present invention may be combined with corticosteroids, such as butteide (budenoside) and dexamethasone (dexamethas〇ne); sulfloxacin; 5-aminosalicylic acid; olsalazine; and agents that interfere with the synthesis or action of proinflammatory cytokines such as IL-1, such as IL-1 beta Transferring enzyme inhibitors and ratio-丨;

T細胞發訊抑制劑例如酪胺酸激酶抑制劑6_氫硫基嘌呤·， IL-11;美沙明（mesalamine);波尼松（prednis〇ne);氮雜硫 嗓呤，氫硫基嘌呤；音氟脈（infliximab);曱基去氫波尼松 號抬酸鈉，二苯氧酸酯/硫酸阿托品（atr〇p suifate);羅普 脈（loperamide)鹽酸鹽；氨曱喋呤；歐美普唾 (omeprazole)，葉酸鹽，希普氟辛（cipr〇fi〇xacin)/ 葡聚糖 _ 水；氫可酮酒石酸氫鹽/apap ;四環素鹽酸鹽；氟辛諾耐 (fluocinonide)，美托尼峻（metronidazole);柳硫汞/爛酸； 消膽胺/蔗糖；希普氟辛鹽酸鹽；莨菪鹼硫酸鹽；美哌咬 (meperidine)鹽酸鹽；咪唑蘭（midazolam)鹽酸鹽；氧可酸j (oxycodone)HCl/ 捕熱息痛；普馬嗓（promethazine)鹽酸 鹽；石粦酸納；石黃甲p号ϋ坐（suifaniethoxazole)/崔抹普凝 (trimethoprim);塞來考昔（celecoxib);聚卡波菲 (polycarbophil)；丙氧吩萘磺酸酯（propoxyphene napsylate);氫可體松（hydrocortisone);綜合維他命；貝沙 奇二鈉（balsalazide disodium);可待因填酸鹽（codeine phosphate)/apap;考來維奋（colesevelam)HCl ;氰可貝明 (cyanocobalamin);葉酸；左敗辛（levofloxacin);甲基去 氫波尼松；納塔魯脈（natalizumab)及干擾素-γ。 可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或 127788.doc -56- 200840567 (IVb)化合物組合用以治療多發性硬化之治療劑非限制性 實例包含下列：皮質類固醇；去氫波尼松；曱基去氫波尼 松；氮雜硫嘌呤；環磷醯胺；環孢素；氨曱喋呤；4-胺基 °比。定；替尼 °定（tizanidine);干擾素 _pia(Avonex® ; Biogen);干擾素-βΐΐ) (Betaseron® ; Chiron/Berlex);干擾 素 an3(Interferon Sciences/ Fujimoto)、干擾素 a(Alfa Wassermann/J&J)、干擾素 βΙΑ-IF (Serono/Inhale Therapeutics)、聚乙二醇化干擾素 a2b(Enzon/Schering-Plough);共聚物 l(Cop-l ; Copaxone®; Teva Pharmaceutical Industries，Inc·);高壓氧；靜脈内免疫球 蛋白；#5皮賓（clabribine);對人類細胞素或生長因子及其 受體之抗體或拮抗劑，例如TNF、LT、IL-1、IL-2、IL-6、IL-7、IL-8、IL-12、IL-23、IL-15、IL-16、ΕΜΑΡ·ΙΙ、 GM-CSF、FGF 及 PDGF。本發明之式（I)、（la)、（II)、 (III) 、（IV)、（IVa)或（IVb)化合物可與對細胞表面分子之抗 體組合如 CD2、CD3、CD4、CD8、CD19、CD20、CD25、 CD28、CD30、CD40、CD45、CD69、CD80、CD86、 CD90或其配位體。本發明之式（I)、（la)、（II)、（III)、 (IV) 、（IVa)或（IVb)化合物亦可與下列藥劑組合：如氨甲喋 呤、環孢素、FK506、雷帕黴素、馬替麥考分酯 (mycophenolate mofetil)、來 I 米特（leflunomide)、NSAID 例如艾普吩、皮質類固醇如去氫波尼松、磷酸二酯酶抑制 劑、腺苦激動劑、抗企栓劑、補體抑制劑、腎上腺劑、藉 前發炎細胞素干擾發訊之藥劑如TNF或IL-1(如IRAK、 127788.doc -57- 200840567 NIK、IKK、p38或MAP激酶抑制劑）、IL-Ιβ轉化酵素抑制 劑、TACE抑制劑、T-細胞發訊抑制劑如激酶抑制劑、金 屬蛋白酶抑制劑、磺沙唤（sulfasalazine)、I雜硫嘌呤、6-氫硫基嗓呤、血管緊張素轉化酵素抑制劑、可溶細胞素受 體及其衍生物（如可溶p55或p75 TNF受體、sIL-lRI、sIL-1RII、SIL-6R)及消炎細胞素（如 IL-4、IL-10、IL-13 及 TGF0)。 可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療多發性硬化之治療劑較佳實例 包含干擾素·β例如INFpla及INFplb ;考普酮（copaxone)、 皮質類固醇、凋亡蛋白酶（caspase)抑制劑例如凋亡蛋白酶-1之抑制劑、IL-1抑制劑、TNF抑制劑、及對CD40配位體 及CD80之抗體。 本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)化 合物亦可與下列藥劑組合：阿土魯脈（alemtuzumab)、朵納 賓諾（dronabinol)、達希魯脈（daclizumab)、米托蒽酮 (mitoxantrone)、山利普丹（xaliproden)鹽酸鹽、法°比口定 (fampridine)、葛崔莫（glatiramer)乙酸鹽、納塔魯脈 (natalizumab)、希納朵（sinnabidol) 、a-免疫激素 (immunokine)NNS03、ABR-215062、AnergiX.MS、趨化 激素受體拮抗劑、BBR-2778、約脈凝（calagualine)、CPI-1189、LEM(微脂體包囊之米托蒽酮）、THC.CBD(類大麻激 動劑）、MBP-8298、美舒潘（mesopram)(PDE4 抑制劑）、 MNA-715、抗-IL-6受體抗體、尼努瓦（neurovax)、吼吩酮 127788.doc -58 - 200840567 別構阱（pirfenidone allotrap)1258(RDP-1258)、sTNF-Rl、 塔蘭斑（talampanel)、特氟脈（teriflunomide)、TGF-P2、替 皮莫泰（tiplimotide)、VLA-4拮抗劑（例如 TR-14035、VLA4 Ultrahaler，Antegran-ELAN/Biogen)、干擾素γ拮抗劑及il- 4激動劑。T cell signaling inhibitors such as tyrosine kinase inhibitor 6_Hhenylthioguanidine, IL-11; mesalamine; prednis〇ne; azathiazepine, thiophanate ;infliximab; thiol dehydropondenide sodium, diphenoxylate / atropine (atr〇p suifate); loperamide hydrochloride; ammoxime; Omeprazole, folate, cipr〇fi〇xacin/glucan _ water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide , metronidazole; sulphur merchandise / rotten acid; cholestyramine / sucrose; sipfluramine hydrochloride; sulphate sulphate; meperidine hydrochloride; midazolam salt Acid salt; oxycodone HCl / caloric acid; promethazine hydrochloride; sodium sulphate; scutellaria psu squat (suifaniethoxazole) / cui sulphur condensate (trimethoprim) ; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; integrated vitamin ; balsalazide disodium; codeine phosphate/apap; colesevelam HCl; cyanobobamin; folic acid; levofloxacin; Methyl dehydroponenon; natalizumab and interferon-gamma. It can be used in combination with the compound of the formula (I), (la), (II), (III), (IV), (IVa) or 127788.doc-56-200840567 (IVb) of the present invention for the treatment of multiple sclerosis Non-limiting examples of agents include the following: corticosteroids; dehydroprednisone; sulfhydryl dehydropondensone; azathiopurine; cyclophosphamide; cyclosporine; aminoguanidine; 4-amine ratio . Titanidine; interferon_pia (Avonex®; Biogen); interferon-βΐΐ) (Betaseron®; Chiron/Berlex); interferon Sciences/ Fujimoto, interferon a (Alfa) Wassermann/J&J), interferon beta ΙΑ-IF (Serono/Inhale Therapeutics), pegylated interferon a2b (Enzon/Schering-Plough); copolymer l (Cop-l; Copaxone®; Teva Pharmaceutical Industries, Inc ·); hyperbaric oxygen; intravenous immunoglobulin; #5 piggybin (clabribine); antibodies or antagonists of human cytokines or growth factors and their receptors, such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, ΕΜΑΡ·ΙΙ, GM-CSF, FGF and PDGF. The compound of the formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention may be combined with an antibody against a cell surface molecule such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or a ligand thereof. The compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention may also be combined with agents such as methotrexate, cyclosporine, FK506, rapa Mycophenolate mofetil, leflunomide, NSAID such as eptophene, corticosteroids such as dehydropononone, phosphodiesterase inhibitors, adenosine agonists, anti-suppositories , complement inhibitors, adrenal agents, agents that interfere with signaling by proinflammatory cytokines such as TNF or IL-1 (eg IRAK, 127788.doc -57-200840567 NIK, IKK, p38 or MAP kinase inhibitors), IL-Ιβ Transforming enzyme inhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, I-hypothiamidine, 6-hydroxythiopurine, angiotensin transformation Enzyme inhibitors, soluble cytokine receptors and their derivatives (such as soluble p55 or p75 TNF receptor, sIL-1RI, sIL-1RII, SIL-6R) and anti-inflammatory cytokines (such as IL-4, IL-10) , IL-13 and TGF0). A preferred embodiment of a therapeutic agent which can be used in combination with a compound of the formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention for treating multiple sclerosis comprises interferon • β such as INFpla and INFplb; copaxone, corticosteroids, caspase inhibitors such as inhibitors of caspase-1, IL-1 inhibitors, TNF inhibitors, and CD40 coordination Antibody to CD80. The compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) according to the invention may also be combined with the following agents: alemutuzumab, doñabino (dronabinol), daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, sodium Natalizumab, sinnabidol, a-immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonist, BBR-2778, calagualine, CPI-1189, LEM (metabody encapsulated mitoxone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti- IL-6 receptor antibody, neurovax, porphin 127788.doc -58 - 200840567 pirfenidone allotrap 1258 (RDP-1258), sTNF-Rl, talampanel, special Teriflunomide, TGF-P2, tiplimotide, VLA-4 antagonist (eg TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon Il- 4 antagonists and agonists.

可與本發明之式（I)、（la)、（II)、（in)、（iv)、（IVa)或 (IVb)化合物組合用以治療心絞痛之治療劑非限制性實例 包含下列·阿斯匹靈、硝'基甘油、異山梨醇（isosorbide)單 硝酸鹽、美托普醇（metoprolol)琥珀酸鹽、氨醯心安 (atenolol)、美托普醇酒石酸鹽、氨莫地平（atnl〇dipine)苯 石黃酸鹽、地替忍（diltiazem)鹽酸鹽、異山梨醇二硝酸鹽、 氣吡多（clopidogrel)硫酸氫鹽、尼非地平（nifedipine)、阿 托瓦絲達汀（atorvastatin)鈣、氯化鉀、氟希脈 (furosemide)、希瓦絲達汀（Simvastatin)、維拉帕米 (verapamil)HCl、毛地黃（digoxin)、心得安（propran〇i〇i)鹽 酸鹽、卡維地醇（carvedilol)、利辛諾皮（nsinopril)、螺内 酯（spironolactone)、鹽酸噻嗪（hydrochlorothiazide)、因諾 拉普（enalapril)馬來酸鹽、納多醇（nad〇l〇i)、蘭米皮 (ramipril)、因諾帕凝（enoxaparin)鈉、肝素鈉、瓦沙坦 (valsartan)、舒塔醇（sotalol)鹽酸鹽、吩諾非伯酸酯 (fenofibrate)、因奇替脈（ezetimibe)、普滅他奈 (bumetanide)、羅舒坦（losartan)鉀、利辛諾皮/鹽酸σ塞嗓、 非羅地平（felodipine)、卡托平（captopril)及雙普醇 (bisoprolol)富馬酸鹽。 127788.doc •59- 200840567 可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療僵直性脊椎炎之治療劑非限制 性實例包含下列：艾普吩、地羅吩納（diclofenac)、米舒普 托（misoprostol)、納普森、美羅希肯（meloxicam)、消炎 痛、地羅芬納、塞來考昔、羅氟考昔、磺沙嗓、氨甲嗓 呤、氮雜硫17票呤、米語環素（minocyclin)、波尼松、恩特 納色及音氟脈。Non-limiting examples of therapeutic agents that can be used in combination with the compounds of formula (I), (la), (II), (in), (iv), (IVa) or (IVb) of the present invention for the treatment of angina include the following Spirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, ammodipine (atnl〇 Dipine) benzoate, diltiazem hydrochloride, isosorbide dinitrate, clopidogrel hydrogen sulphate, nifidipine, atorvastatin Calcium, potassium chloride, furosemide, Simvastatin, verapamil HCl, digoxin, propran〇i〇i hydrochloric acid Salt, carvedilol, nsinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nad〇l〇 i), ramirril, enoxaparin sodium, heparin sodium, valsartan, sulphate Sotalol hydrochloride, fenofibrate, ezetimibe, bumetanide, losartan potassium, licinin/hydrochloride Indole, felodipine, captopril and bisoprolol fumarate. 127788.doc •59- 200840567 may be used in combination with a compound of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) according to the invention for the treatment of ankylosing spondylitis Non-limiting examples of therapeutic agents include the following: Apoptin, diclofenac, misoprostol, Napson, meloxicam, indomethacin, diphenfena, and sputum Rarex, Rofluoxetine, saponin, methotrexate, aza-sulfur 17-vomit, minocyclin, ponisone, Entner, and fluoride.

可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療氣喘之治療劑非限制性實例包 含下列：舒喘靈（albuterol)、沙美特醇（salmeterol)/氣替卡 松（fluticasone)、孟魯斯特（montelukast)鈉、氟替卡松丙酸 鹽、布地奈德（budesonide)、波尼松、沙美特醇辛納酸鹽 (salmeterol xinafoate)、雷瓦特醇（levalbuterol)HCl、硫酸 舒喘靈/艾普托平（ipratropium)、去氫波尼松、填酸納、乙 醯替崔胺希諾酮（triamcinolone acetonide)、貝羅美沙松 (beclomethasone)二丙酸鹽、漠化艾普托平、氣硫黴素 (azithromycin)、σ比普特醇（pirbuterol)乙酸鹽、去氫波尼 松、無水茶鹼、甲基去氫波尼松、琥拍酸鈉、克拉黴素 (clarithromycin)、安可來片（zafirlukast)、法莫特醇 (formoterol)富馬酸鹽、流感病毋疫田、氨莫希林 (amoxicillin)三水合物、氣尼舒來（fluniso丨ide)、過敏注 射、色甘酸鈉、非舒吩納啶（feX〇fenadine)鹽酸鹽、氟尼舒 來/薄荷醇、氨莫希林/卡瓦魯奈（clavulanate)、左氣辛 (levofloxacin)、吸入器輔助裝置、脈吩尼辛 127788.doc -60- 200840567 (guaifenesin)、地塞米松（dexamethasone)石粦酸鈉、莫希氣 辛（moxifloxacin)HCl、鹽酸去氧環素（doxycycHne hyclate)、脈吩尼辛 /d-美沙分（methorphan)、ρ·麻黃驗 /c〇d/ 氯吩尼（chlorphenir)、葛替氣辛（gatifloxacin)、色替嗓 (cetirizine)鹽酸鹽、莫美塔松（mometasone)^ σ南酸鹽、沙 美特醇辛納酸鹽、苯佐納醋（benzonatate)、色菲辛 (cephalexin)、pe/氫可酮/氯吩尼、色替嗪HC1/偽麻納敏 (pseudoephed) > 去氧腎上腺素/cod/普美唤 (promethazine)、色普奇（cefprozii)、地塞米松、胍吩尼辛/ 偽麻黃驗、氣吩尼明（chlorpheniramine)/氫可嗣、尼多羅 米（nedocromil)納、特丁琳（terbutaline)硫酸鹽、腎上腺 素、甲基去氫波尼松及異丙喘寧（metapr〇teren〇i)硫酸鹽。 可與本發明之式（I)、（la)、（Π)、（in)、（iv)、（IVa)或 (IVb)化合物組合用以治療c〇pD之治療劑非限制性實例包 含下列：舒喘靈硫酸鹽/溴化艾普托平、沙美特醇/氟替卡 松、舒喘靈、沙美特醇辛納酸鹽、氟替卡松丙酸鹽、波尼 松、無水余驗、曱基去氫波尼松、琥珀酸鈉、孟魯斯特 納、布地奈德、法莫特醇富馬酸鹽、乙醯替崔胺希諾酮、 左氟辛、脈吩尼辛、氮硫黴素、貝羅美沙松二丙酸鹽、雷 瓦特醇HC1、氟尼舒來、色崔呤酮（ceftriax〇ne)鈉、氨莫希 林三水合物、葛替氟辛、安可來片、氨莫希林/卡瓦魯 奈、氟尼舒來/薄荷醇、氯吩尼明/氫可酮、異丙喘寧硫酸 鹽、曱基去氫波尼松、莫美塔松呋喃酸鹽、麻黃鹼/e〇d/ 氯吩尼、吼普特醇乙酸鹽、p_麻黃鹼/羅拉特啶 127788.doc -61 - 200840567 (loratadine)、特丁啉硫酸鹽、溴化替歐托平（ti〇tr〇pium bromide)、（R，R)-法莫特醇、TgAAT、希羅米拉特 (cilomilast)及羅氟米拉特（r0fiuinilast)。 可與本發明之式⑴、（ia)、（n)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療HCV之治療劑非限制性實例包Non-limiting examples of therapeutic agents that can be used in combination with the compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention for the treatment of asthma include the following: Albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, ponisone, salmeterol Sodium sulphate (salmeterol xinafoate), levalbuterol HCl, salbutamol sulphate/ipratropium, dehydropondensone, sodium chlorate, triamcinolone acetonide ), beclomethasone dipropionate, desertified eptopine, azithromycin, σ pubuterol acetate, dehydroponenol, anhydrous theophylline, Methyl dehydroponectin, sodium sulphonate, clarithromycin, zafirlukast, formoterol fumarate, influenza plague, ammonia oxicillin Amoxicillin) trihydrate, fluniso丨ide, allergy injection, sodium cromoglycate, non FeX〇fenadine hydrochloride, flunixol/menthol, ammonia/clavulanate, levofloxacin, inhaler aid, pulse fensin 127788 .doc -60- 200840567 (guaifenesin), dexamethasone sodium citrate, moxifloxacin HCl, doxycyc HH hyclate, pulse phenoxine/d-methas Methorphan), ρ·麻黄检/c〇d/chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone^ σ sulphate , salmeterol octanoate, benzonatate, phenexin, pe/hydrocodone/chlorpheniramine, coloriazine HC1/pseudoephed > deoxygenation Adrenaline/cod/promethazine, cefprozii, dexamethasone, 胍menisin/pseudo-ephedrine, chlorpheniramine/hydroquinone, nidolomide Nedocromil), terbutaline sulfate, adrenaline, methyl dehydroponenon and ipraphanine (metapr〇teren〇i) sulfur Acid salt. Non-limiting examples of therapeutic agents that can be used in combination with the compounds of formula (I), (la), (Π), (in), (iv), (IVa) or (IVb) of the present invention for the treatment of c〇pD include the following : salbutamol sulfate / epopodamine bromide, salmeterol / fluticasone, salbutamol, salmeterol octanoate, fluticasone propionate, ponisone, anhydrous residual, thiol dehydrogenation Nisson, sodium succinate, montelstein, budesonide, farotropin fumarate, acetaminophen quinolone, levofloxacin, pulse phenoxine, nitrofuramycin, shellfish Lomethasone dipropionate, Revastatol HC1, flunixen, ceftriax〇ne sodium, aminomosislin trihydrate, gatifloxacin, encola tablets, aminomosis Cavaluna, flunix/menthol, clonidine/hydrocodone, isoproterenol sulfate, sulfhydryl dehydroprednisone, mometasone furanoate, ephedrine/e 〇d/ clophene, ciprofloxacin acetate, p_ephedrine/ralatidine 127788.doc -61 - 200840567 (loratadine), terbutin sulphate, tetopodbate (ti〇tr 〇pium bromide), (R, R)- Famote alcohol, TgAAT, cilomilast and roflumilat (r0fiuinilast). Non-limiting example package of therapeutic agents useful in the treatment of HCV in combination with a compound of formula (1), (ia), (n), (III), (IV), (IVa) or (IVb) of the present invention

含下列：干擾素-a-2a、干擾素-a-2b、干擾素-a c〇nl、干 擾素-a-ni、聚乙二醇化干擾素·a_2a、聚乙二醇化干擾素· a-2b、利巴偉寧（ribavirin)、聚乙二醇干擾素a_2b+利巴偉 寧、熊去氧膽酸（ursodeoxycholic acid)、甘草酸、胸腺素 (thymalfasin)、馬索明（Maxamine)、νχ·497及經由介入下 列藥劑而用以治療HCV之任何化合物：Hcv聚合酶、hcv 蛋白酶、HCV螺旋酶及HCV IRES(内部核糖體進入部位）。 可與本發明之式⑴、（Ia)、（„)、⑽、（IV)、（iVa)或 (IVb)化合物組合用以治療特發性肺纖維化之治療劑非限 制性實例包含下列：波尼松、氮雜硫嗓呤、舒喘靈、可奇 辛（colchicine)、硫酸舒喘靈、毛地黃、γ干擾素、曱基去 氫波尼松琥㈣納、隸其潘（wazepam)、ι希脈、利辛 諾皮硝基甘油、螺内r曰、環磷醯胺、溴化艾普托平、放 射線黴素d(actinomycin d)、卩可姓心… )α特麵（alteplase)、氟替卡松 丙酸鹽、左氟辛、異丙喘寧琉酸 L馼鹽、嗎啡硫酸鹽、氧可酮 HC1、氯化鉀、乙醯替崔 胺希諾酮、無水塔羅姆 (taCr〇limus)、鈣、干擾素 α、氨 ^ ^ . . ν 丸Τ喋呤、馬替麥考分酯及 干擾素-γ-1 β。 可與本發明之式（I)、（la)、 (11)、（III)、（IV)、（IVa)或 127788.doc ·62· 200840567 (IVb)化合物組合用以治療心肌梗塞之治療劑之非限制性 實例包含下列：阿斯匹靈、硝基甘油、美托普醇酒石酸 鹽、因諾帕凝鈉、肝素鈉、氯咄多硫酸氫鹽、卡維地醇、 舒％靈、嗎啡硫酸鹽、美托普醇琥珀酸鹽、苄丙酮香豆素 鈉、利辛諾皮、異山梨醇單硝酸鹽、毛地黃、氟希脈、希 瓦絲達、/丁、蘭米皮、泰尼特酶（tenecteplase)、因諾拉普馬 來酸鹽、妥希脈（torsemide)、利塔酶（retavase)、羅舒坦 斜、啥納皮（quinapril) HCl/mag carb、普滅他奈、阿特 、因納拉皮特（enalaprilat)、阿米達酮（amiodarone)鹽酸 鹽、替羅啡般（tirofiban)HCl單水合物、地替忍鹽酸鹽、卡 托平、艾貝沙坦（irbesartan)、瓦沙坦（valsartan)、心得安 鹽酸鹽、法辛皮（fosinopril)鈉、利多卡因鹽酸鹽、艾替菲 貝泰（eptifibatide)、色法寧（cefazolin)納、阿托品硫酸鹽、 胺基己酸、螺内酯、干擾素、舒塔醇鹽酸鹽、氣化鉀、多 古薩（docusate)鈉、多普明（dobutamine)HCl、歐普哇蘭 (alprazolam)、帕瓦絲達丁（pravastatin)鈉、阿托瓦絲達汀 躬、米朵蘭（midazolam)鹽酸鹽、馬哌啶（meperidine)鹽酸 鹽、異山梨醇二硝酸鹽、腎上腺素、多巴胺鹽酸鹽、吡瓦 魯啶（bivalirudin)、羅舒瓦絲達汀（|*〇81^381&以11)、因奇替 脈/希瓦絲達汀、阿瓦舒脈（avasimibe)及卡吼普賴 (cariporide) 〇 可與本發明之式（I)、(la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療牛皮癣之治療劑非限制性實例 包含下列·· #5普三烯（calcipotriene)、羅貝舒（clobetasol)丙 127788.doc -63- 200840567Contains the following: interferon-a-2a, interferon-a-2b, interferon-ac〇nl, interferon-a-ni, pegylated interferon·a_2a, pegylated interferon·a-2b , ribavirin, peginterferon a_2b+ribavirin, ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, maxamine, νχ·497 And any compound used to treat HCV via interventions in the following agents: Hcv polymerase, hcv protease, HCV helicase, and HCV IRES (internal ribosome entry site). Non-limiting examples of therapeutic agents that can be used in combination with the compounds of formula (1), (Ia), („), (10), (IV), (iVa) or (IVb) of the present invention for the treatment of idiopathic pulmonary fibrosis include the following: Bonizon, azathiazepine, salbutamol, colchicine, salbutamol sulfate, foxglove, gamma interferon, sulfhydryl dehydroponisone succinate (tetra) nat, lisaki (wazepam ), ι希脉, Licinol nitroglycerin, snail ruthenium, cyclophosphamide, epopodamine bromide, actinomycin d, 卩可姓心...)α特面(alteplase) ), fluticasone propionate, levofloxacin, propofol citrate L sulfonium salt, morphine sulphate, oxycodone HC1, potassium chloride, acetamidine thioxanthone, anhydrous tartan (taCr〇) Limus), calcium, interferon alpha, ammonia ^ ^ . . ν Τ喋呤 Τ喋呤, martini glutamate and interferon-γ-1 β. Can be combined with the formula (I), (la), (11) , (III), (IV), (IVa) or 127788.doc · 62 · 200840567 (IVb) Compound combinations Non-limiting examples of therapeutic agents for treating myocardial infarction include the following: aspirin, nitroglycerin, Topolol tartrate, inaopa sodium, heparin sodium, chlorinated polysulfate, carvedilol, sulphate, morphine sulfate, metoprolol succinate, benzylacetone coumarin sodium, Licinino, isosorbide mononitrate, foxglove, fluixine, shivasida, / butyl, lammyid, tenecteplase, inolapromide, Torsemide, retavase, rosothine, quinapril HCl/mag carb, panitamin, ate, enalaprilat, amiodarone Hydrochloride, tirofiban HCl monohydrate, destinol hydrochloride, captopine, irbesartan, valsartan, propranol hydrochloride, method Fosinopril sodium, lidocaine hydrochloride, eptifibatide, cefazolin, atropine sulfate, aminocaproic acid, spironolactone, interferon, sultanol hydrochloride Salt, potassium carbonate, docusate sodium, dobutamine HCl, alprazolam, Pavasida (pravastatin) sodium, atorvastatin, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, adrenaline, dopamine hydrochloride, pyriva Ival 啶 b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b b Non-limiting examples of therapeutic agents for treating psoriasis in combination with a compound of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) according to the invention include the following · #5普三三等(calcipotriene), 罗贝舒(clobetasol)丙127788.doc -63- 200840567

酸鹽、乙酸替崔胺希諾酮、鹵貝舒（halobetasol)丙酸鹽、 塔ϋ坐稀（tazarotene)、氨甲嗓呤、氣辛諾耐、增量之貝他美 松（betamethasone)二丙酸鹽、乙醯替敗辛諾酮 (fluocinolone acetonide)、阿希崔汀（acitretin)、樹皮洗髮 精（tar shampoo)、貝他美松戊酸鹽、莫美塔松ϋ夫喃酸鹽、 嗣康嗤（ketoconazole)、潘莫辛（pramoxine)/氟辛諾酮、氫 可體松戊酸鹽、氟蘭崔諾賴（flurandrenolide)、尿素、貝他 美松、羅貝舒丙酸鹽/軟化劑（emoll)、氟替卡松丙酸鹽、 氮硫黴素、氫可體松、保濕配方、葉酸、地奈德 (desonide)、°比莫羅姆（pimecrolimus)、焦炭、二氟松 (diflorasone)二乙酸鹽、恩特納色葉酸鹽、乳酸、曱氧沙 練（methoxsalen)、he/舒葛鉍（bismuth subgal)/諾斯（ζηοχ)/ 利舒（resor)、甲基去氫波尼松乙酸鹽、波尼松、防曬劑、 氣氣松（halcinonide)、水楊酸、蒽林（anthralin)、羅可托酮 (clocortolone)特戊酸鹽、煤炭萃取物、焦炭/水楊酸、焦 炭/水楊酸/硫、地舒美松（des〇ximetas〇ne)、地忍潘 (diazepam)、軟化劑、氟辛諾耐/軟化劑、礦物油/藥麻 油/na lact、礦物油/花生油、石油/肉莖蔻酸異丙酯、普舒 蘭（psoralen)、水楊酸、皂/三漠莎蘭（tribr〇msaian)、^硫 汞/硼酸、塞來考昔、音I脈、環孢素、歐法= (alefacept)、艾法鲁脈（efalizumab)、塔羅姆、吡莫 PUVA、UVB及磺舒嗪。 ' ' 可與本發明之式⑴、（Ia)、（II)、⑽、（iv)、（iva)或 (岡化合物組合用以治療牛皮癖關節炎之冶療劑非限制 127788.doc 200840567 性實例包含下列：4甲4吟、恩特納色、隸考昔、塞來 考昔、葉酸、確料、納普森、來I米特、甲基去氯波尼 松乙酸鹽、消炎痛、羥基氯喹硫酸鹽、波尼松、舒林酸 (sulmdac)、★曾里之貝他美松二丙酸鹽、音氟脈、氨曱喋 呤、葉酸鹽、乙醯替崔胺希諾酮、二氯吩納、二Acid salt, tigliflozin acetate, halobetasol propionate, tazarotene, methotrexate, gas sinuo, incremental betamethasone II Propionate, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone valproate , ketoconazole, pramoxine/flucinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, robepapropionate /softener (emoll), fluticasone propionate, nitrothiamycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coke, diflurazone Diacetate, Enterna folate, lactic acid, methoxsalen, bismuth subgal/ζηοχ/resor, methyl dehydrogenation Nisson acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, rococodone (clocortol One) pivalate, coal extract, coke/salicylic acid, coke/salicylic acid/sulfur, desemimesone (des〇ximetas〇ne), diazepam, softener, flincinolone/ Softener, mineral oil / sesame oil / na lact, mineral oil / peanut oil, oil / meat stem isopropyl citrate, psoralen, salicylic acid, soap / tribr〇msaian, ^ Mercury/boric acid, celecoxib, syringol I, cyclosporine, eufacept, efalizumab, taroma, pyromofluorene PUVA, UVB and sulfostazine. ' ' can be combined with the formula (1), (Ia), (II), (10), (iv), (iva) or (the combination of the compounds of the present invention for the treatment of psoriatic arthritis non-limiting 127788.doc 200840567 sex Examples include the following: 4 A 4 吟, Entner color, rituximab, celecoxib, folic acid, indeed, Napson, Imit, methyl desperipenone acetate, indomethacin, Hydroxychloroquine sulfate, prednisone, sulindac (sulmdac), betazepam, betamethasone dipropionate, fluorescein, ammoxime, folate, acetaminophen quinolone Dichlorophene, two

砜、吡羅希肯、二氯吩納鈉、酮普吩、美羅希肯、甲基去 氫波尼松、納普美酮、妥美汀（tGlmetin)鈉、約普三稀、環 孢素、二氣吩納鈉/米舒普特、氟辛諾耐、葡糖胺硫酸 鹽、硫代韻果酸金鈉、氫可體松酒石酸氫鹽/apap、艾普 吩、利塞朵奈鈉（risedronate sodium)、磺二嗪、硫胍、瓦 待考昔、歐法色及艾法鲁脈。 可與本發明之式⑴、（Ia)、（ΪΙ)、（ΙΠ)、、（^)或 (IVb)化合物組合用以治療再阻塞之治療劑非限制性實例 包含下列：希羅姆（sir〇limus)、帕希塔（paclitaxel)、艾羅 利姆（everolimus)、塔羅姆、ABT_578及捕熱息痛。 可與本發明之式（I)、（la)、（II)、QIi)、（IV)、（IVa)或 (IVb)化合物組合用以治療坐骨神經痛之治療劑非限制性 實例包含下列：氫可體松酒石酸氫鹽/apap、羅氟考昔、環 苯扎林（cyCl〇benzaPTine)HCl、甲基去氫波尼松、納普森、 艾普吩、氧可酮HC1/消炎痛、塞來考昔、瓦待考昔、甲基 去氫波尼松乙酸鹽、波尼松、可待因磷酸鹽/apap、特莫朵 HC1/消炎痛、美塔噚酮（metaxai〇ne)、美羅希肯、美卡莫 (methocarb疆〇1)、利多卡因鹽酸鹽、二氯吩鈉、葛巴配汀 (gabapentin)、地塞米松、卡舒普醇（cariSOpr〇d〇i)、_ σ各酸 127788.doc •65- 200840567 胺丁三醇（ketorolac tromethamine)、消炎痛、捕熱息痛、 地忍潘、納普美酮、氧可酮HC1、替尼啶HC1、二氯吩鈉/ 米舒普托、丙氧吩萘石黃酸鹽/apap、sas/氧可（OXyC〇d)/氧可 酮ter、艾普吩/氫可酮bit、特莫朵HC1、艾妥多羅、丙氧吩 HC1、阿米替林HC1、卡舒普醇/可待因磷酸鹽/asa、嗎啡硫 酸鹽、綜合維他命、納普森鈉、歐菲納寧 檬酸鹽及泰莫潘（temazepam)。 可與本發明之式（I)、（la)、（II)、（III)、（IV)、（IVa)或 (IVb)化合物組合用以治療SLE(狼瘡）之治療劑較佳實例包 含下列：NSAIDS例如二氣吩、納普森、艾普吩、吡羅希 肯、消炎痛；COX2抑制劑例如塞來考昔、羅氟考昔、瓦 待考昔；抗瘧疾藥例如羥基氣喹；類固醇類例如波尼松、 去氫潑尼松、布替耐德、地塞米松；細胞毒素例如氮雜硫 嘌呤、環磷醯胺、嗎替麥考酚酯、氨甲喋呤；PDE4之抑 制劑或嘌呤合成抑制劑例如Cellcept®。式（I)、（la)、（II)、 (III)、（IV)、（IVa)或（IVb)化合物亦可與下列組合：績舒 嗓、5_胺基水楊酸、歐沙唤、Imuran®及干擾前發炎細胞 毒素如IL-1合成、製造或作用之藥劑，例如凋亡蛋白酶抑 制劑如IL-1 /3轉化酵素抑制劑及IL-lra。式（I)、（la)、 (II)、（III)、（IV)、（IVa)或（IVb)化合物亦可與T細胞發訊抑 制劑組合，例如酪胺酸激酶抑制劑；或可標靶丁細胞活化 分子之分子例如CTLA-4-IgG或抗-B7族群抗體、抗-PD-1族 群抗體。式（I)、（la)、（II)、（III)、（IV)、（IVa)或（IVb)化合 物可與IL-11或抗-細胞素抗體組合，例如法諾妥魯脈 127788.doc -66- 200840567 (fonotolizumab)(抗-IFNg抗體）、或抗-受體之受體抗體例 如抗-IL-6受體抗體及對B-細胞表面分子之抗體。式（I)、 (la)、（II)、（III)、（IV)、（IVa)或（IVb)化合物亦可與下列組 合：LJP 394(阿貝替姆（abetimus))、可耗竭或去活化B -細 胞之藥劑，例如利土脈（抗-CD20抗體）、制淋巴細胞-B(抗-BlyS抗體）、TNF拮抗劑例如抗-TNF抗體、D2E7(PCT公開 號 WO 97/29131 ; HUMIRAtm)、CA2 (REMICADEtm)、 CDP 571、TNFR-Ig架構物、（p75TNFRIgG (ENBRELTM)及 p55TNFRIgG (LENERCEPTtm)。 本發明組合物中，該活性化合物若需要可與其他可相容 醫藥活性成分聯合。例如，本發明化合物可與已知可治療 本文所述疾病或病症之其他治療劑組合投藥。例如，與一 或多種可抑制或避免VEGF或血管生成素產生、弱化對 VEGF或血管新生素的細胞内反應、阻斷細胞内訊號傳 遞、抑制血管通透性增高、減低發炎、或抑制或避免形成 紅腫或新血管新生之其他醫藥劑組合。本發明化合物可在 該其他醫藥劑之前、之後或同時投藥，只要投藥過程適 當。該其他醫藥劑包含（但不限於）抗紅腫固醇類、 NSAIDS、ras抑制劑、抗-TNF劑、抗-IL1劑、抗組織胺、 PAF-拮抗劑、COX-1抑制劑、COX-2抑制劑、NO合成酶抑 制劑、Akt/PTB抑制劑、IGF-1R抑制劑、PKC抑制劑、PI3 激酶抑制劑、約調蛋白（calcineurin)抑制劑及免疫壓抑 劑。本發明化合物與該其他醫藥劑以加成方式或相乘方式 作用。因此，投與此等物質組合抑制金管新生、血管通透 127788.doc -67- 200840567 性增高或抑制水腫形成對於高度增生疾病、血管新 生:血管通透性增高或水種可提供比單獨投與各物質更大 舒緩效^。在治療惡性疾病中，與抗增生劑或細胞毒性化 干療d或放射線治,療之組合包含在本發明範圍内。 或夕洋本發明化合物可以可治療或舒緩本文所述疾病 或病症之劑量，以本身對人類病患投藥或與生物上適宜之 载^或賦合之醫藥組合物對人類病患投藥。該等化 U物之扣σ物亦可以簡單混合物或於適宜調配之醫藥組合 物對病患投藥。治療有效劑量代表^以產生避免或弱化本 文所述疾病或病症之化合物或諸化合物量。_配本發明化 合物及投藥之技術可見於本技藝所悉知之參考文獻，例如Sulfone, piroxicam, sodium diclofenac, ketoprofen, meroxigen, methyl dehydroponenon, nalmemedone, tGlmetin sodium, hexapril, cyclosporine , two-gas sodium/misopropt, flucinolone, glucosamine sulfate, sodium thiosodium citrate, hydrogen hexanoate, apat, apap, ipose, lysedona Sodium (risedronate sodium), sulfodiazine, thioindigo, valdoxib, oufa and efalu. Non-limiting examples of therapeutic agents that can be used in combination with the compounds of formula (1), (Ia), (ΪΙ), (ΙΠ), (^) or (IVb) of the present invention for the treatment of reocclusion include the following: sir 〇limus), paclitaxel, everolimus, tarom, ABT_578 and paracetamol. Non-limiting examples of therapeutic agents that can be used in combination with the compounds of formula (I), (la), (II), QIi), (IV), (IVa) or (IVb) of the present invention for the treatment of sciatica comprise the following: hydrogen Physic acid tartrate/apap, rofluoxetine, cyproterilin (cyCl〇benzaPTine) HCl, methyl dehydropondenis, apisone, ipprom, oxycodone HC1/indomethacin, stopper Ricoxib, valdecoxib, methyl dehydropononine acetate, ponisone, codeine phosphate/apap, temodo HC1/indomethacin, metaxai〇ne, mero Heiken, mekamo (methocarb 〇 1), lidocaine hydrochloride, sodium dichlorophene, gabapentin, dexamethasone, carbamazepine (cariSOpr〇d〇i), _ σ 酸 127788.doc •65- 200840567 ketorolac tromethamine, indomethacin, paracetamol, tonbens, nalmemedone, oxycodone HC1, tenridine HC1, sodium dichlorophene / misoproto, propoxyphene naphthyl phosphate / apap, sas / oxygen (OXyC〇d) / oxycodone ter, eptophene / hydrocodone bit, temodo HC1, icotyrolol , propoxyphene HC1, amitripty HC1 is, Ka Shupu alcohol / codeine phosphate / ASA, morphine sulfate, multivitamins, Na Pusen sodium, citric acid and Tai Mopan Oufeinaning (temazepam). Preferred examples of therapeutic agents which can be used in combination with the compounds of the formula (I), (la), (II), (III), (IV), (IVa) or (IVb) of the present invention for the treatment of SLE (lupus) include the following : NSAIDS such as diphene, Napson, Apoptin, piroxicam, indomethacin; COX2 inhibitors such as celecoxib, rofluoxoxib, valecoxib; anti-malarial drugs such as hydroxyquine; steroids Such as prednisone, deprednisone, budesonide, dexamethasone; cytotoxins such as azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or hydrazine synthesis Inhibitors such as Cellcept®. Compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may also be combined with the following: gibberidine, 5-aminosalicylic acid, ousha , Imuran® and agents that interfere with the synthesis, manufacture or action of proinflammatory cytotoxins such as IL-1, such as apoptosis protease inhibitors such as IL-1/3 invertase inhibitors and IL-lra. a compound of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may also be combined with a T cell signaling inhibitor, such as a tyrosine kinase inhibitor; A molecule that targets a target cell activation molecule is, for example, a CTLA-4-IgG or an anti-B7 group antibody, an anti-PD-1 group antibody. A compound of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may be combined with an IL-11 or an anti-cytokine antibody, such as farotolu 127788. Doc-66-200840567 (fonotolizumab) (anti-IFNg antibody), or an anti-receptor receptor antibody such as an anti-IL-6 receptor antibody and an antibody against a B-cell surface molecule. Compounds of formula (I), (la), (II), (III), (IV), (IVa) or (IVb) may also be combined with LJP 394 (abetimus), depletable or An agent that deactivates B-cells, such as a striatum (anti-CD20 antibody), a lymphocyte-B (anti-BlyS antibody), a TNF antagonist such as an anti-TNF antibody, D2E7 (PCT Publication No. WO 97/29131; HUMIRAtm), CA2 (REMICADEtm), CDP 571, TNFR-Ig framework, (p75 TNFR IgG (ENBRELTM) and p55 TNFR IgG (LENERCEPTtm). In the compositions of the invention, the active compound can be combined with other compatible pharmaceutically active ingredients if desired. For example, a compound of the invention can be administered in combination with other therapeutic agents known to treat the diseases or conditions described herein, for example, with one or more cells that inhibit or prevent VEGF or angiopoietin production, attenuate cells against VEGF or angiogenesis. Internal reaction, blocking intracellular signal transmission, inhibiting increased vascular permeability, reducing inflammation, or inhibiting or avoiding the formation of redness or neovascularization. Other compounds of the invention may be before, after or simultaneously with the other pharmaceutical agent Dosing As long as the administration process is appropriate, the other pharmaceutical agents include, but are not limited to, anti-red steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF-antagonists, COX-1 inhibition. Agent, COX-2 inhibitor, NO synthase inhibitor, Akt/PTB inhibitor, IGF-1R inhibitor, PKC inhibitor, PI3 kinase inhibitor, calcineurin inhibitor and immunosuppressive agent. The compound interacts with the other pharmaceutical agent in an additive manner or in a multiplicative manner. Therefore, administration of such a combination inhibits the neovascularization of the tube, vascular permeability, 127788.doc-67-200840567, or inhibits edema formation for highly proliferative diseases, blood vessels. Newborn: increased vascular permeability or water can provide greater relief than administration of each substance alone. In the treatment of malignant diseases, combined with anti-proliferative agents or cytotoxic dry treatments or radiation therapy, Within the scope of the invention, or a compound of the invention may be used to treat or soothe the dosage of the disease or condition described herein, in a pharmaceutical composition which is itself administered to a human patient or is biologically compatible or formulated. Administration of a drug to a patient. The drug may also be administered to a patient in a simple mixture or in a suitably formulated pharmaceutical composition. The therapeutically effective dose represents a compound which produces a compound or which avoids or attenuates the disease or condition described herein or Amounts of the compounds. The techniques of formulating the compounds of the invention and administering them can be found in the references well known in the art, for example

Remington, PharmaCeutical Sciences,- Ma〇k Publishing C〇·，Easton，PA，最終版本。 醫藥組合物及投藥模式 適宜之投藥路徑可包含例如口服、眼睛滴入、直腸、經 黏膜：局部或腸内投藥；非經腸胃輸送包含肌肉内、皮 *脊髓内主射、以及椎官内'直接腦室内、靜脈内、腹 膜内、鼻腔内、或眼睛内注射。 或者’可以局部而非全身性方式投與化合物，例如經由 2合物直接注射入水腫（edemat_)位置，且通常係以點 滴衣或持續釋出之調配物注射。 再者’可於標㈣物輸送系統中投藥，例如以以塗佈有 内皮麵胞-特異抗體之微脂體。 本發明之醫藥組合物可依本身已知之方式製造，例如藉 127788.doc -68- 200840567 由習知之混合、溶解、造粒、製造糖衣、粉碎、乳化、包 囊、膜包覆法或凍乾製程。 依據本發明使用之醫藥組合物因此可以習知方式，使用 一或多種包括有助於活性化合物加工成$醫藥上可使用之 製劑之赋形劑及助劑之生理上可接受之載劑而調配。適當 之調配物取決於選擇之投藥路徑。 田Remington, PharmaCeutical Sciences, - Ma〇k Publishing C〇·, Easton, PA, final version. Appropriate route of administration of the pharmaceutical composition and mode of administration may include, for example, oral administration, ocular instillation, rectal, transmucosal: topical or enteral administration; parenteral delivery includes intramuscular, cutaneous* spinal injection, and intrauterine Direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injection. Alternatively, the compound can be administered in a local rather than systemic manner, such as by direct injection into the edema_e position via the conjugate, and is typically injected as a drip or sustained release formulation. Further, the drug can be administered in a standard (four) delivery system, for example, to a liposome coated with an endothelial cell-specific antibody. The pharmaceutical compositions of the present invention can be made in a manner known per se, for example by conventional mixing, dissolving, granulating, sugar-making, comminuting, emulsifying, encapsulating, film coating or lyophilization, by way of 127788.doc-68-200840567. Process. The pharmaceutical compositions for use in accordance with the present invention may thus be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate the processing of the active compounds into preparations which are pharmaceutically acceptable. . The appropriate formulation will depend on the route of administration chosen. field

就注射而言，本發明之藥劑可調配於水溶液中，較好調 配於生理上可接受之緩衝液中如漢克氏（Hanksi)溶液、林 格式（Ringer，S)溶液或生理食鹽水緩衝液。就經黏膜投藥而 言’調配物中使用對欲滲透之障壁為適宜之滲透劑。該渗 透劑通常為本技藝中已知。 就口服投藥而言，可藉由合併活性化合物及本技藝中習 知之醫藥可接f性載劑輕易的調配。該等載劑可使本發明 之化合物調配成供待治療之病患口服吞嚥之錠劑、藥丸、 糖衣錠、膠囊、液體、凝膠、糖漿、漿料、懸浮液等。口 服^用之醫藥製劑可藉由合併活性化合物及固體賦形劑， 視情況研磨所得之混合物且若需要添加適宜之助劑後將細 顆粒此合物加工，以獲得錠劑或糖衣錠蕊。適宜之賦形劑 :^ 、充诏如糖包含乳糖、蔗糖、甘露糖醇或山梨糖 ，纖隹素氣劑例如玉米澱粉、小麥澱粉、稻米澱粉、馬 鈴薯澱粉、明膠、特加康斯膠、甲基纖維素、經基丙基甲 基纖維素、藉其田 (PVP)。若需要^ 2纖、准素納及/或水乙稀基吼略唆嗣 习 f」添加崩解劑如交聯聚乙烯基吡咯啶_、 瓊膠、或褐藻酸或其鹽如褐藻酸鈉。 127788.doc -69- 200840567 糖衣錠蕊係提供有適宜包衣。就該目的而言，可使用濃 細糖洛液’其可視情況含有阿拉伯膠、滑石、聚乙烯基。比 咯啶酮、卡波姆膠（carb〇p〇i gei)、聚乙二醇及/或二氧化 鈦' 漆料溶液及適宜之有機溶劑或溶劑混合物。錠劑或糖 衣包衣中可添加染料或顏料以辨識或特性化活性化合物劑 量之不同結合物。For injection, the agent of the present invention can be formulated in an aqueous solution, preferably in a physiologically acceptable buffer such as Hanksi solution, Ringer (S) solution or physiological saline buffer. . In the case of transmucosal administration, a suitable penetrant for the barrier to be infiltrated is used in the formulation. Such penetrants are generally known in the art. For oral administration, it can be easily formulated by combining the active compound with a pharmaceutical which is known in the art. Such carriers allow the compound of the present invention to be formulated into lozenges, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral swallowing of a patient to be treated. The pharmaceutical preparation for oral administration can be processed by combining the active compound and a solid excipient, optionally grinding the resulting mixture and, if necessary, adding a suitable auxiliary agent to obtain a tablet or a sugar-coated core. Suitable excipients: ^, filling such as sugar containing lactose, sucrose, mannitol or sorbose, fibrin gas such as corn starch, wheat starch, rice starch, potato starch, gelatin, tecancons, Methyl cellulose, propyl propyl methyl cellulose, borrowed from the field (PVP). If it is necessary to add a disintegrating agent such as crosslinked polyvinylpyrrolidine, agar, or alginic acid or a salt thereof, such as sodium alginate, is required to add a disintegrating agent such as crosslinked polyvinylpyrrolidine. . 127788.doc -69- 200840567 The dragee core is provided with a suitable coating. For this purpose, it is possible to use a concentrated sugar liquor, which may optionally contain gum arabic, talc, or polyvinyl. Pyrrolidone, carbomerium (carbicarb), polyethylene glycol and/or titanium dioxide paint solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the lozenge or dragee coating to identify or characterize different combinations of active compound doses.

可口服使用之醫藥製劑包含由明膠製成之推套式膠囊 (push-fit capsules)以及由明膠及可塑劑如甘油或山梨糖醇 製成之軟質、密封膠囊。推套式膠囊可含有與填充劑如乳 糖、結合劑如澱粉、及/或潤滑劑如滑石或硬脂酸鎂及視 情況選用之安定劑預混合之活性成分。軟質膠囊中，活性 化合物可溶解或懸浮於適宜之液體中如脂肪油、液態鏈烷 或液悲聚乙二醇。另外，可添加安定劑。口服投藥之所有 調配物應為適合該投藥之劑量。 就頰内投藥而言’組合物可以依習知方式調配之錠劑或 喉片之形式服用。 〆 入投藥而言’本發明使用之化合物係以自加壓袋或 霧化：之氣溶膠噴霧形式，配合使用適宜之推進劑例如二 ::氟甲&、三氯氟甲烷、二氯四氟乙烷、二 他適宜之氣體適當的輸送1為加壓之氣溶膠，則劑= :可精由裝設_以輪送計量之量決定。吸 所用之例如明膠之膠囊或藥s可經調配成含有二= 、且：粉劑基質如乳糖或澱粉之粉劑混合物。 該專化合物可針對藉注射例如點滴瓶注射或持續灌入之 127788.doc 200840567 非經腸胃投藥調配。注射用調配物可提出為單位劑量形式 例如安瓿或多劑量容器並添加保存劑。該等組合物可以如 在油性或水性載體中之懸浮液、溶液或乳液形式服用，且 可含有調配劑如懸浮劑、安定劑及/或分散劑。 非、、二％月技藥之醫藥調配物包含水溶性形式之活性化合 物之水洛液。此外，活性化合物之懸浮液可製備成適宜之 油性注射懸浮液。適宜之親脂性溶劑或載體包含脂肪油如Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-on capsules may contain the active ingredient premixed with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, a liquid alkane or a liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in dosages suitable for the administration. For buccal administration, the composition can be administered in the form of a lozenge or lozenge formulated in a conventional manner. For the purpose of injecting into the drug, the compound used in the present invention is in the form of a self-pressurizing bag or an atomized aerosol spray, and a suitable propellant such as fluorocarbon &chloroform; methylene chloride; Fluorine, the appropriate gas for the appropriate delivery of 1 is a pressurized aerosol, then the agent =: fine can be determined by the amount of installation _ in turn. Capsules or medicines such as gelatin for use in absorbing can be formulated into a powder mixture containing two = and: a powder base such as lactose or starch. The specific compound can be formulated for parenteral administration by injection, for example, by trickle injection or continuous infusion of 127788.doc 200840567. Formulations for injection can be presented in unit dosage form such as ampoules or multi-dose containers with the addition of a preservative. The compositions may be administered as a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The pharmaceutical formulation of the non-, two-month technical drug comprises a water-soluble solution of the active compound in a water-soluble form. In addition, suspensions of the active compounds can be prepared in a suitable oily injection suspension. Suitable lipophilic solvents or carriers include fatty oils such as

芝麻油或合成脂肪酸酯如油酸乙酯或三酸甘油酯，或微脂 體。水性注射懸浮液可含有增加懸浮液黏度之物質，如羧 基甲基纖維錢、山梨糖醇或葡聚糖。視情況，該懸浮液 亦可合適宜之安定劑或增加化合物溶解度之藥劑，使之可 製備高濃度溶液。 或者活性成分可為在使用前以適宜之載體例如殺菌之 無熱源水加以構成之粉劑形式。 所該等化合物亦可調配成直腸用組合物如含有習知栓劑基 、可可亞奶，由或其他甘油酯之栓劑或留置型灌腸劑。 “月〕述之调配物外，《等化合物亦可調配成儲器製劑。 此長效型調配物可藉由植人（例如皮下或肌肉内植入或肌 :内注射)投藥。因此，例如化合物可與適宜之聚合性或 &水性物質（例如在可接受油中之乳液）或離子交換樹脂調 配，或調配成難溶解之衍生物如難溶解鹽。 δ月之‘水性化合物之醫藥用載劑實例為包括苄基 輔：:咖界面活性劑、水可相容之有機聚合物及水相之 輔-劑系統。該輔溶劑系統可為 127788.doc -71 - 200840567Sesame oil or a synthetic fatty acid ester such as ethyl oleate or triglyceride, or a liposome. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may be formulated with a suitable stabilizer or an agent which increases the solubility of the compound to provide a high concentration solution. Alternatively, the active ingredient may be in the form of a powder in the form of a suitable carrier such as sterilized non-pyrogenic water prior to use. The compounds may also be formulated in rectal compositions such as conventional suppository bases, cocoa milk, or other glyceride suppositories or indwelling enemas. In addition to the formulations described in the "Month", "etc. compounds may also be formulated into a reservoir formulation. This long-acting formulation may be administered by implantation (eg subcutaneous or intramuscular implantation or intramuscular injection). Thus, for example The compound may be formulated with a suitable polymerizable or aqueous substance (for example, an emulsion in an acceptable oil) or an ion exchange resin, or may be formulated as a poorly soluble derivative such as a hardly soluble salt. Examples of the carrier include a benzoic acid:: coffee surfactant, a water compatible organic polymer, and an aqueous phase auxiliary system. The auxiliary solvent system can be 127788.doc -71 - 200840567

3% w/v苄基醇、8% w/v非極性界面活性劑聚山梨糖醇酯 (polysorbate) 80及65% w/v聚乙二醇4〇〇，以無水乙醇補充 至所需體積之溶液。該VPD辅溶劑系統（VPD:5W)由經含 5%葡萄糖之水溶液稀釋成！：〗之νΡΕ>所組成。此輔溶劑系 統可使疏水性化合物充分溶解，且本身在全身投藥後產生 低毒性。當然，輔溶劑系統之性質可在不破壞其溶解度及 毒性特性之下大幅改變。另外，輔溶劑成分之一致性可被 改變：例如可使用其他低毒性非極性界面活性劑代替聚山 梨糖醇酯80;可改變聚乙二醇之部份尺寸；可使用其他生 物可相容之聚合物代替聚乙二醇，例如聚乙烯基吡咯啶 酮；且可使用其他醣類或多醣類取代葡聚糖。 或者，可使用疏水性醫藥化合物用之其他輸送系統。微 脂體及乳液為疏水性藥物用輸送載體或載劑之習知實例。 亦可使用某些有機溶劑如二甲基亞颯，但通常付出毒性較 大之代價。此外，該等化合物可使用持續釋出之系統輪 送，如含有該治療劑之固態疏水性聚合物之半滲透基質。 各種㈣釋出之物f已經被建立且為熟悉本技藝者所習 知。持續釋出之膠囊可依其化學性質釋出化合物歷時數週 至超過100天。依治療試劑之化學性質及生物安定性而 定：：使用額外之蛋白質安定方法。 /亥等酉藥組合物亦可包括適宜之固體或凝膠相載劑或職 7 d該载劑或賦形劑之實例包含（但不限於)碳酸鈣、磷 酸#5、各種播、、m W泰、纖維素衍生物、明膠及聚合物如聚 乙二醇。 127788.doc -72- 200840567 月之卉夕化合物可以與醫 提供。醫藥w拉/ 接文性相斟雜2 商桌可接党性鹽 目對離子之鹽 於）鹽酸'^ /夕種酸形成，包含％ 生 …乙酸、乳酸、酒石酸、鞋3(但不限 專。鹽在水性或其他質子溶劑中比 乂、果酸、丁二酸 更可溶之傾向。 ’、應之游離鹼形式有 、、用於本發明之醫藥組合物包含其 成分以達到其預期目的之組合物。尤t I有效量之活性3% w/v benzyl alcohol, 8% w/v non-polar surfactant polysorbate 80 and 65% w/v polyethylene glycol 4 〇〇, replenished to the required volume with absolute ethanol Solution. The VPD co-solvent system (VPD: 5W) is diluted with an aqueous solution containing 5% glucose! :〗 〖 ΡΕ ΡΕ gt. This co-solvent system allows the hydrophobic compound to be sufficiently dissolved and itself to produce low toxicity after systemic administration. Of course, the nature of the co-solvent system can vary drastically without destroying its solubility and toxicity characteristics. In addition, the consistency of the co-solvent component can be changed: for example, other low-toxic non-polar surfactants can be used instead of polysorbate 80; the size of the polyethylene glycol can be changed; other biocompatible can be used. The polymer replaces polyethylene glycol, such as polyvinylpyrrolidone; and other sugars or polysaccharides can be used in place of the glucan. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be used. Microlipids and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl hydrazine may also be used, but usually at the expense of greater toxicity. In addition, such compounds can be delivered using a system of sustained release, such as a semi-permeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various (iv) released objects f have been established and are known to those skilled in the art. Sustained release capsules can release compounds for several weeks to over 100 days depending on their chemical nature. Depending on the chemical nature and biostability of the therapeutic agent: Use additional protein stabilization methods. / 酉 酉 et al such as a suitable solid or gel phase carrier or 7 d. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, phosphoric acid #5, various sowing, m W, cellulose derivatives, gelatin and polymers such as polyethylene glycol. 127788.doc -72- 200840567 The plant of the month can be provided with the doctor. Medicine w pull / textual phase noisy 2 business table can be connected to the party salt salt on the ion salt in the hydrochloric acid '^ / evening acid formation, including % raw ... acetic acid, lactic acid, tartaric acid, shoes 3 (but not limited The salt is more soluble in hydrazine, fruit acid, or succinic acid in aqueous or other protic solvents. ', the free base form, the pharmaceutical composition used in the present invention contains its ingredients to achieve its intended purpose. The composition of the compound

對於預防欲治療標的之現有病症之發展^有效量意指 劑量里之决疋為熟悉本技藝者之能力所了解。 就本發明方法中所用之化合物而言， 由細胞分析估算。例如，可依細胞及動:模 镱ξ丨丨Μ與、曲 糾切镆型調配劑量以 度範圍’其包含在細胞分析中測定之％❶(亦 尸達，）既定受體活性之最大抑制之—半之試驗化合物濃 又）。某些情況T，宜在3至5%血清蛋白存在下測定ECs〇, 因為該測定約等於血漿蛋白質結合至該化合物之結合作 用。可使用該資料更精確的決定人類使用之劑量。再者， 全身性投藥之有利化合物可以血漿中可安全達到之量有效 調控完整細胞中之Sip族之受體。 治療有效量係指使病患之病症獲得改善之化合物量。該 等化合物之毒性及療效可藉由標準醫藥程序，以細胞培養 物或試驗動物測定，例如用於測定最大耐受劑量（MTD)及 ED5〇(50%最大反應之有效劑量）。毒性及療效間之劑量比 為治療指數且其可以MTD及ED5〇間之比表示。以可展現高 127788.doc -73- 200840567 治療指數之化合物較佳。由此等細胞培養物分析及動物研 九獲彳于之數據可用於調配人類使用之劑量範圍。該等化合 物之劑量較好在有少許或無毒性之包含EDsg之循環濃度範 圍内。該劑量可依使用之劑型及利用之投藥路徑在該範圍 内改變。確實之調配物、投藥路徑及劑量可由各醫師考量 病患之症狀選擇。（例如見Fingl以w，1975，in，，TheThe development of an existing condition for the prevention of a subject to be treated means that the dosage is determined by the ability of those skilled in the art. For the compounds used in the methods of the invention, they are estimated by cellular analysis. For example, the dosage can be adjusted according to the cell and the movement: the sputum and the stencil type in the range of 'the maximum inhibition of the established receptor activity determined by the % ❶ (also corpse, measured in the cell analysis) - half of the test compound is strong and). In some cases, it is preferred to measure ECs in the presence of 3 to 5% serum protein, as this assay is approximately equal to the binding of plasma proteins to the compound. This information can be used to more accurately determine the dose used by humans. Furthermore, the beneficial compounds for systemic administration can effectively regulate the receptors of the Sip family in intact cells in amounts that are safely achieved in plasma. A therapeutically effective amount refers to the amount of a compound that results in an improvement in the condition of the patient. The toxicity and efficacy of such compounds can be determined by cell culture or test animals by standard pharmaceutical procedures, for example, to determine the maximum tolerated dose (MTD) and ED5(R) (50% maximal effective dose). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between MTD and ED5. Preferably, the compound exhibiting a therapeutic index of 127788.doc -73-200840567 is preferred. The data obtained from such cell culture analysis and animal studies can be used to formulate dose ranges for human use. The dose of such compounds is preferably within the range of circulating concentrations of EDsg containing little or no toxicity. The dosage can vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by the physician to consider the symptoms of the patient. (See, for example, Fingl, w, 1975, in,, The

Pharmac〇l〇gical Basis 〇f Therapeutics"，Ch」川。在處理Pharmac〇l〇gical Basis 〇f Therapeutics", Ch” Chuan. Processing

危機上，投與接近MTD之急性丸粒或灌注對於獲得快速之 反應可能有利。 劑量及投藥間隔可個別調整以提供足以調控sip族之受 體之活11基團之血漿量’或為最小有效濃度。 將隨著各化合物而.變，但可自體外數據估算；例如，使用 本文所述之分析達到抑制天然配位體結合之5〇_9〇%所需之 艰度達到MEC所而之劑量將取決於個體特性及投藥路 徑。然而，可使践咖分析或生物分析以敎血裝濃 劑量投藥間隔亦可使用MEC值測定。化合物應使用該時 可維持血漿量高於MEC之_%，較好在他辦❶之間， 且更好在5〇撕。之間之絲㈣，直到達到病症期望之改 善為止。若為局部投藥或選擇性攝取，則藥物之有效 濃度可能與血漿濃度無關。 ㈣之組合物量當絲決於欲治療之標的、該標的體 重、惟患嚴重性、投藥方式及臨床醫師之判斷。 若需要，該等組合物可呈現為含有-或多個含活性成分 127788.doc -74- 200840567 之單位劑型之包裝或分配器中。該包裝可例如包括金屬或 塑膠箔如鼓泡包裝（blister pack)。該包裝袋或分配器可附 加投藥指示單。亦可製備在可相容醫藥載劑中調配二包括 本發明化合物之組合物，置於適宜容器 之治療。 且“不適應症 列舉之調配物 在某些調配物中’使用極小尺寸之顆粒形式，例如以产 體此1研磨所獲得之本發明化合物可能係有利的。 使用本發明化合物製造醫筚 中。在此4"… 以、、且合物係說明於下列敘述 中在此敘述中，名詞”活性化合物” 人舲 士、甘e *义 物代表本發明之任何化 ό物，尤其疋先珂實例之一 a) 膠囊 之-終產物之任何化合物。 在膠囊之製備中，可使1〇重 舌旦於叙々3址么 里伤數之活性化合物與240 重里伤數之礼糖解凝聚且摻 膠膠囊中，各膠囊均含有單I㈣混合物充填於硬質明 化合物。 劑®或部份單位劑量之活性 b) 鍵劑 鍵劑可由（例如）下 列成份製 重量份數 活性化合物 10 乳糖 190 玉米澱粉 22 聚乙烯基咄咯啶_ 10 硬脂酸鎂 3 127788.doc -75 - 200840567 使活性化合物、乳糖及部分澱粉解凝聚、掺合且以含聚 乙稀基料相之乙醇溶液將所得混合物製成粒狀。使乾 燥之顆粒與硬Μ鎂及其餘澱粉掺合1著於打錠機中壓 製混合物’獲得各含有單位劑量或部分單位劑量活性化合 物之鍵劑。 C)腸包衣旋 可經由上述（b)所述之方法製備錠劑。該錠劑可使用含 20%纖維素乙酸酯苯二甲酸酯及3%苯二甲酸二乙酯之乙 醇·一氯甲烧（1:1)溶液，依習知方式進行腸包衣。 d)栓劑 在栓劑之製備中，可例如將1〇〇重量份數之活性化合物 摻入1300重量份數之三酸甘油酯栓劑基劑中且使混合物形 成各含有治療有效量活性成分之栓劑。 本备明亦包括式（I)、（la)、（H)、（JH)、（IV)、（IVa)或 (IVb)化合物作為藥品之用途。 本盔明另一態樣係提供一種式⑴、（Ia)、（H)、（jn)、 (IV)、（IVa)或（Ivb)化合物或其鹽在製造供治療哺乳類，尤 其疋人類之血管通透性過高症（vascular hyperpenneability)、 與血官新生有關之疾病、增生性疾病及/或免疫系統疾病 之藥品方面之用途。 本發明亦提供一種治療血管通透性過高症、不當心血管 生成 &生性疾病及/或免疫系統疾病之方法，該方法包 括對有需要之哺乳動物，尤其是人類投與治療有效量之式 ⑴、Ua)、（Π)、（III)、（IV)、（IVa)或（IVb)化合物。 127788.doc •76- 200840567 所有參考文獻，包含期刊、專利及公開之專利申請案之 教示均以全文以引用方式併入本文中。 S1P受體GThS分析 [35S]GTPYS結合分析可使用閃爍近似分析法 (scintillation proximity assay)(SPA)及過濾、法二者進行。該 二格式均在96孔盤中且利用獲自過度表現SIP!、S1P2、 S1P3、S1P4或S1P5之穩定或暫時CHO人類細胞株之細胞 膜。化合物料液係使用DMSO構成10 mM且使用100% DMSO進行連續稀釋。將化合物轉移至96孔盤中對所有分 析產生1% DMSO終濃度（對100微升分析體積為1微升）。冷 凍之細胞膜經解凍並稀釋於含20 mM HEPES pH 7.4、0.1% 不含脂肪酸之BSA、100 mM NaCl、5 mM MgC!2及 1 〇 μΜ GDP之分析緩衝液中。對SPA分析而言，細胞膜與WGA-SPA珠粒混合以產生每孔5微克細胞膜及500微克珠粒之最 終濃度。就過濾分析而言，將細胞膜直接添加至培養盤中 每孔5微克。此分析藉由添加50微升細胞膜或細胞膜/珠粒 混合物至分析盤之各孔中而開始。接著，於各孔中添加50 微升0.4 nM [35S]GTPyS並培育30分鐘。使用10 μΜ未標記 之GTPyS測量非特異結合。就SPA分析而言，使該盤旋轉 且接著在Topcount上讀取。就過濾分析而言，使用Packard 96孔收取器使該盤收取至GF-C過濾盤上。 【33P]S1P結合至S1P受體之抑制作用 使用獲自過度表現S1P〗、S1P2、S1P3、S1P4或S1P5之暫 時轉染之HEK細胞之細胞膜進行放射性配位體結合。所有 127788.doc -77- 200840567 化合物溶於DMSO中且添加至分析缓衝液之前進行連續稀 釋。最終分析DMSO濃度為1% (v/v)。[33P]S1P購自Perkin Elmer且於所有分析中以50 pM使用。使冷凍之細胞膜解凍 並再懸浮於含 50 mM HEPES pH 7.4、100 mM NaCl、10 mM MgCl2及0.1%不含脂肪酸之BSA之分析緩衝液中。添 加細胞膜獲得每孔5-10微克之細胞膜。在冷卻1 μΜ S1P存 在下測定非特異結合。在室溫進行培育45-60分鐘後，使 用Packard 96孔收取器過濾至GF-C過濾盤上。該等盤乾燥 後於各孔中添加Microscint，密封並在Topcount上計數。 間寫 ACN 乙腈 CHC13 氯仿 C02 二氧化碳 DBAD 偶氮二曱酸二-第三丁酯 DBU 1，8-二氮雜雙環（5.4.0)十一碳-7-烯 DCC N，N’-二環己基碳二醯亞胺 DIAD 偶氮二甲酸二異丙酯 Dibal-H 二異丁基氫化鋁 DIC N，N’-二異丙基碳二醯亞胺 DIEA N，N-二異丙基乙胺 DMA N，N-二甲基乙醯胺 DMF N，N-二甲基甲醯胺 DMSO 二甲基亞颯 EDCI 1-(3-二甲胺基丙基）-3-乙基碳二醯亞胺 127788.doc -78- 200840567In crisis, it may be advantageous to invest in an acute pellet or perfusion close to the MTD for a rapid response. The dosage and dosing interval can be adjusted individually to provide a plasma amount sufficient to modulate the live 11 group of the sip family or to be the minimum effective concentration. It will vary with each compound, but can be estimated from in vitro data; for example, the dose required to achieve the inhibition of natural ligand binding by 5 〇 〇 〇 〇 达到 达到 达到 达到 达到 达到 达到Depending on individual characteristics and route of administration. However, it is also possible to use a MEC value to determine whether the coffee or the bioassay can be administered at a dose of blood. The compound should be used to maintain a plasma level higher than _% of the MEC, preferably between the sputum, and preferably at 5 〇. Between the silk (four), until the desired improvement of the disease is achieved. In the case of topical administration or selective ingestion, the effective concentration of the drug may be independent of plasma concentration. (4) The amount of the composition depends on the target to be treated, the weight of the target, the severity of the disease, the mode of administration, and the judgment of the clinician. If desired, such compositions may be presented in a package or dispenser containing one or more unit dosage forms containing the active ingredient 127788.doc-74-200840567. The package may, for example, comprise a metal or plastic foil such as a blister pack. The package or dispenser may be accompanied by a dosing instruction sheet. Compositions comprising a compound of the invention in a compatible pharmaceutical carrier may also be prepared for treatment in a suitable container. And "the formulations listed in the non-indications" may be advantageous in the form of particles of very small size in certain formulations, for example, the compounds of the invention obtained by the grinding of the body. The compounds of the invention are used in the manufacture of a medical order. In the following description, the term "active compound" in the following description, the term "active compound", the gentleman, the glycine * represents the chemical of any of the present invention, especially the first example One of a) Any compound of the capsule-final product. In the preparation of the capsule, the active compound of 1 〇 舌 于 于 々 々 々 々 々 々 々 々 々 々 々 々 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 240 In capsules, each capsule contains a single I (d) mixture filled with a hard compound. Agent ® or part of a unit dose of activity b) A bond agent can be, for example, the following ingredients in parts by weight of active compound 10 lactose 190 corn starch 22 Vinylpyrrolidine_ 10 Magnesium stearate 3 127788.doc -75 - 200840567 Deagglomeration, blending of active compound, lactose and some starches and ethanol solution containing polyethylene phase The resulting mixture is granulated. The dried granules are blended with hard magnesium sulphate and the rest of the starch. The mixture is compressed in a tableting machine to obtain a key agent each containing a unit dose or a part of a unit dose of the active compound. Spinning can be prepared by the method described in the above (b). The tablet can be used with 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol and monochloromethane. (1:1) solution, enteric coating according to conventional methods. d) Suppositories In the preparation of suppositories, for example, 1 part by weight of the active compound can be incorporated into 1300 parts by weight of triglyceride suppository base. And forming a mixture into a suppository each containing a therapeutically effective amount of the active ingredient. The preparation also includes a compound of formula (I), (la), (H), (JH), (IV), (IVa) or (IVb) For use as a medicine. Another aspect of the present invention is to provide a compound of the formula (1), (Ia), (H), (jn), (IV), (IVa) or (Ivb) or a salt thereof for the manufacture of a mammal for treatment. , especially in human vascular hyperpenneability, diseases associated with blood-surgery, Use of a drug for a sexually transmitted disease and/or an immune system disease. The present invention also provides a method for treating vascular hyperpermeability, inappropriate cardiovascular production &/or malignant diseases and/or immune system diseases, the method comprising A mammal, especially a human, is required to administer a therapeutically effective amount of a compound of formula (1), Ua), (Π), (III), (IV), (IVa) or (IVb). 127788.doc •76- 200840567 All references The literature, including the teachings of the journals, patents, and published patent applications, is hereby incorporated by reference in its entirety. S1P Receptor GThS Analysis [35S] GTPYS binding assays can be performed using both scintillation proximity assay (SPA) and filtration. Both formats were in 96 well plates and utilized cell membranes obtained from stable or transient CHO human cell lines overexpressing SIP!, S1P2, S1P3, S1P4 or S1P5. Compound stocks were made up to 10 mM using DMSO and serially diluted using 100% DMSO. Compounds were transferred to 96-well plates for a final concentration of 1% DMSO for all analyses (1 microliter for 100 microliters of assay volume). The frozen cell membrane was thawed and diluted in assay buffer containing 20 mM HEPES pH 7.4, 0.1% fatty acid free BSA, 100 mM NaCl, 5 mM MgC! 2 and 1 〇μΜ GDP. For SPA analysis, cell membranes were mixed with WGA-SPA beads to produce a final concentration of 5 micrograms of cell membrane per well and 500 micrograms of beads per well. For filtration analysis, the cell membrane was added directly to 5 micrograms per well in the plate. This analysis was initiated by adding 50 microliters of cell membrane or cell membrane/bead mixture to each well of the assay disk. Next, 50 μl of 0.4 nM [35S]GTPyS was added to each well and incubated for 30 minutes. Non-specific binding was measured using 10 μΜ unlabeled GTPyS. For SPA analysis, the disk is rotated and then read on the Topcount. For filtration analysis, the disc was charged to a GF-C filter disc using a Packard 96-well retriever. [33P] Inhibition of binding of S1P to S1P receptor Radioligand binding was carried out using a cell membrane obtained from transiently transfected HEK cells overexpressing S1P, S1P2, S1P3, S1P4 or S1P5. All 127788.doc -77- 200840567 compounds were dissolved in DMSO and serially diluted prior to addition to assay buffer. The final assay was to have a DMSO concentration of 1% (v/v). [33P]S1P was purchased from Perkin Elmer and used at 50 pM in all analyses. The frozen cell membrane was thawed and resuspended in assay buffer containing 50 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, and 0.1% fatty acid free BSA. Cell membranes were added to obtain 5-10 micrograms of cell membrane per well. Non-specific binding was determined in the presence of 1 μΜ of S1P cooled. After incubation for 45-60 minutes at room temperature, it was filtered onto a GF-C filter disk using a Packard 96-well collector. After the disks were dried, Microscint was added to each well, sealed and counted on a Topcount. Inter-write ACN acetonitrile CHC13 chloroform CO 2 carbon dioxide DBAD bis-tert-butyl phthalate DBU 1,8-diazabicyclo (5.4.0) undec-7-ene DCC N, N'-dicyclohexyl Carbodiaimine DIAD Diisopropyl azodicarboxylate Dibal-H Diisobutylaluminum hydride N DIC N,N'-Diisopropylcarbodiimide DIEA N,N-Diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl hydrazine EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 127788.doc -78- 200840567

EtOAcEtOAc

Et3N HBTU HATU HC1 HOBt HOAT HPLC MeOH NaOH PS-DCC PS-PPh3 RBF RP Rt THF i-PrOH PPh3 SFC SOCl2 乙酸乙酯 三乙胺 0- 苯并三唑-1-基-N，N，N’，N’-四甲基脲鑌六氟 磷酸鹽 〇-(7·氮雜苯并三唑-1-基）-N，N，N’，N’-四甲基 脲鏽六氟磷酸鹽 鹽酸 1- 羥基苯并三唑 1- 羥基-7-氮雜苯并三唑 高性能液體層析 甲醇 氫氧化鈉 聚合物支撐之碳二醯亞胺 聚合物-支撐之三苯基膦 圓底瓶 逆相 駐留時間 四氫咬喃 2- 丙醇 三苯基膦 超流體層析 亞硫酿氣 分析方法 分析數據於通用程序中定義或於實例之表中定義。除非 I27788.doc -79- 200840567 另有說明，否則所有1Η或13C NMR數據均於VarianEt3N HBTU HATU HC1 HOBt HOAT HPLC MeOH NaOH PS-DCC PS-PPh3 RBF RP Rt THF i-PrOH PPh3 SFC SOCl2 ethyl acetate triethylamine 0-benzotriazol-1-yl-N,N,N',N '-Tetramethylurea quinone hexafluorophosphate 〇-(7·azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea rust hexafluorophosphate hydrochloride 1- Hydroxybenzotriazole 1-hydroxy-7-azabenzotriazole high performance liquid chromatography methanol sodium hydroxide polymer supported carbon diimine polymer-supported triphenylphosphine round bottom bottle reverse phase residence Time tetrahydrogenate 2-propanol triphenylphosphine superfluidic chromatography sulfurous gas analysis method analytical data is defined in a general procedure or defined in the table of the examples. All 1Η or 13C NMR data are in Varian unless otherwise stated in I27788.doc -79- 200840567

Mercury Plus 400 MHz或Bruker DRX 400 MHz設備上收 集；化學位移係以每百萬份（ppm)被引用。高壓液體層析 (HPLC)分析數據於實驗中詳列或參考HPLC條件的表，使 用表1中下方情況的方法字母。 表1· HPLC法之列示 方法 HPLC條件 除非另有說明，否則移動相A為1〇 乙酸銨，移動相B為Collected on Mercury Plus 400 MHz or Bruker DRX 400 MHz equipment; chemical shifts are quoted in parts per million (ppm). High pressure liquid chromatography (HPLC) analysis data is detailed in the experiment or reference to the HPLC conditions table, using the method letters in the lower case in Table 1. Table 1. List of HPLC methods HPLC conditions Unless otherwise stated, mobile phase A is 1 乙酸 ammonium acetate and mobile phase B is

a ----- HPLC等級乙腈 5-95% B歷時3·7分鐘而維持在95% B歷時1分鐘(ι·3毫升/分 鐘流速）。4加5〇 mm Z〇rbax XDB CIS管柱(5 μπι粒子）。偵測 方法為二極體陣列(DAD)及蒸發光散射(ELSD)偵測以及正/ 負電子喷霧離子化。 b c 5_60% B歷時1·5分鐘接著60_95% B至2·5分鐘而維持在95〇/〇 b 歷，1.2分鐘(1·3毫升/分鐘流速)。4·6χ3〇麵Vydac Genesis C8管柱(4 μηι粒子）。偵測方法為二極體陣列(DA〇)及蒸發光 散射(ELSD)偵測以及正/負電子噴霧離子化。 …X 鐘流速）。4.心3〇 mm Vydae Genesis CS管柱(4 μπι粒子）。偵測 方法為二極體陣列(DAD)及蒸發光散射(ELSD)偵測以及正/負 電子喷霧離子化。 ' d 30-95% B歷時2·0分鐘而維持在95% B歷時1.5分鐘(1 ·〇毫升/分 鐘流速）。UY λ=210-360 麵；Genesis C8, 4 μιη，30x4.6 mm管 柱；ESI+ve/-ve) e 使用乙腈(B)及含0.1%三氟乙酸之水(八)的1〇_1〇〇%梯度，流 速為I·5毫升/分鐘(0-0.1分鐘10% A，〇·ι_3.1分鐘hm〇〇%b， 3·1-3·9分鐘 100-10% B，3.9-4.0分鐘l〇〇-l〇〇/0 b)。21 mm Phenomenex Luna Combi-HTS C8 (5 μπι粒子）。偵測方法 為二極體陣列(DAD)及蒸發光散射(ELSD)偵測以及处^離 子化。 127788.doc -80- 200840567a ----- HPLC grade acetonitrile 5-95% B lasted for 3.7 minutes and maintained at 95% B for 1 minute (1·3 ml/min flow rate). 4 plus 5 〇 mm Z〇rbax XDB CIS column (5 μπι particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive/negative electron spray ionization. b c 5_60% B lasts for 1.5 minutes and then 60_95% B to 2.5 minutes and is maintained at 95 〇 / 〇 b calendar, 1.2 minutes (1.3 ml / min flow rate). 4·6χ3〇 Vydac Genesis C8 column (4 μηι particles). Detection methods are diode array (DA〇) and evaporative light scattering (ELSD) detection and positive/negative electron spray ionization. ...X clock flow rate). 4. Heart 3〇 mm Vydae Genesis CS column (4 μπι particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive/negative electron spray ionization. 'd 30-95% B lasted for 2.0 minutes and remained at 95% B for 1.5 minutes (1 · 〇 ml / minute flow rate). UY λ=210-360 surface; Genesis C8, 4 μιη, 30×4.6 mm column; ESI+ve/-ve) e 1 〇 using acetonitrile (B) and water containing 0.1% trifluoroacetic acid (eight) 1〇〇% gradient, flow rate is I·5 ml/min (0-0.1 min 10% A, 〇·ι_3.1 min hm〇〇% b, 3·1-3·9 min 100-10% B, 3.9 -4.0 minutes l〇〇-l〇〇/0 b). 21 mm Phenomenex Luna Combi-HTS C8 (5 μπι particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and ionization. 127788.doc -80- 200840567

方法 HPLC條件 示非另有說明，否則移動相Ag1〇mM乙酸銨，移動相6為 —-—HPLC等級乙腈 f 梯度為4分鐘内為5-35% B接著35-95% B至6分鐘而在95% B 維持L7分鐘(ι·3毫升/分鐘流速)。移動相a為含〇 1%甲酸之 水’移動相B為HPLC等級乙腈。層析所用管柱為4.6x30 mm Vydac Genesis C8管柱(4 μιη粒子）。彳貞測方法為二極體陣列 (DAD)及蒸發光散射(ELSD)偵測以及正/負電子噴霧離子 化。The HPLC conditions of the method are not otherwise indicated, otherwise the mobile phase Ag1 〇 mM ammonium acetate, the mobile phase 6 is - HPLC grade acetonitrile f gradient is 5-35% in 4 minutes B then 35-95% B to 6 minutes Maintain L7 minutes at 95% B (1·3 ml/min flow rate). The mobile phase a is water containing hydrazine 1% formic acid. The mobile phase B is HPLC grade acetonitrile. The column used for chromatography was a 4.6 x 30 mm Vydac Genesis C8 column (4 μιη particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive/negative electron spray ionization.

NHNH

反應圖1中說明製備本發明之二-取代π号二峻化合物之方 法（X=CR3或N)。反應圖1步驟i中，使適宜之經取代腈化合 物1(外購或經通用程序A或B製造）與羥基胺反應，獲得化 合物2。此等類型之反應在文獻（例如見Yan，a/.， c& Med CTzem Le" 2006, 16(14)，3 679_3 683)中已充分建立。 該反應通常係在質子性溶劑（如MeOH或EtOH)中，於回流 溫度（如60°C)或低於該溫度下進行。產物2通常藉由濃縮混 合物自反應混合物以固體單離。化合物2可就此使用。步 驟ii顯示使化合物2與適宜之酸或醯氣偶合，接著閉環產生 化合物3。該偶合反應通常在偶合試劑（如HOBt、DCC)存 在下以羧酸進行，或在有機鹼（如DIEA、Et3N)存在下以醯 氯進行，該反應在室溫或升溫（例如20-1 80°C)下，在溶劑 如DMF或DMA中進行。隨後之閉環反應在升溫（例如 160。〇下就地完成（例如見 Wang，ei a/·，Org Le" 2005 7(5)， 127788.doc -81 - 200840567 925-928)。接著單離化合物3且使用標準技術（如逆相液體 層析或SFC)純化。 通用之合成程序 本中請案+揭示之架構主要化合物利之通用反應圖欽 述如下（反應圖1-3)。 合成路徑（通用程序A、B) 反應圖1· 4-烷氧基-苄腈之通用The method of preparing the di-substituted π-di-disaccharide compound of the present invention (X = CR3 or N) is illustrated in Reaction Scheme 1. In step i of Figure 1, a suitable substituted nitrile compound 1 (purchased or manufactured by General Procedure A or B) is reacted with a hydroxylamine to obtain Compound 2. These types of reactions are well established in the literature (see, for example, Yan, a/., c& Med CTzem Le" 2006, 16(14), 3 679_3 683). The reaction is usually carried out in a protic solvent such as MeOH or EtOH at a reflux temperature (e.g., 60 ° C) or below. Product 2 is typically isolated as a solid from the reaction mixture by concentration of the mixture. Compound 2 can be used as such. Step ii shows the coupling of compound 2 with a suitable acid or helium, followed by ring closure to give compound 3. The coupling reaction is usually carried out as a carboxylic acid in the presence of a coupling reagent (such as HOBt, DCC) or as a ruthenium chloride in the presence of an organic base (such as DIEA, Et3N) at room temperature or elevated temperature (eg 20-1 80). Under °C), it is carried out in a solvent such as DMF or DMA. Subsequent ring closure reactions are carried out at elevated temperatures (eg, 160. in situ) (see, for example, Wang, ei a/., Org Le" 2005 7(5), 127788.doc -81 - 200840567 925-928). 3 and purification using standard techniques (such as reverse phase liquid chromatography or SFC). General synthetic procedures. The general scheme of the main compounds in the framework of the application + disclosure is as follows (reaction diagram 1-3). Procedure A, B) Reaction Figure 1 · Generalization of 4-alkoxy-benzonitrile

反應圖2. 3,5_二取代之，二嗤之通用合成路徑（通 C、D及 E) 用程序Reaction Scheme 2. 3,5_Disubstituted, general synthetic path of diterpenes (pass C, D, and E)

(Ο(Ο

力 Η，或(E) 入 R, '---- R-Force, or (E) into R, '---- R-

反應圖3· S藍氣之通用合成路徑（通用程序f) 又Reaction Figure 3. S-blue gas general synthetic path (general procedure f)

R OH (F) ΟR OH (F) Ο

通用程序之列示 通用程序A :使用三苯基膦製備4_燒氧基_节猜 通用程序B:使用與聚合物結合之三苯基膦二 苄腈 通用程序C:羥基脒之製備 通用程序D:自酸形成噚二唑 通用程序E:自醯氣形成噚二唑 通用程序F :自酸形成醯氣 127788.doc •82- 200840567 通用程序G:自猜形成路 通用程序Η :醛之胺化作用 通用程序I :以丙烯酸酯使吲哚烷化 通用程序J :以溴化物使吲哚烷化 通用程序Κ:第三丁酯之去保護 通用程序L:芳基鹵之胺化作用 通用程序Μ:炫基漠及紛之Mitsonubu反應 通用程序N :脫苄基作用 通用程序Ο:經保護I，2-二醇之去保護 通用程序應用之實例 通用程序之字母編碼構成最終產物之合成路徑。如何決 定路徑之實務例係使用實例A33作為非限制說明提供於後 文。實例A33，4-[3·(3-氣異丙氧基·笨基）_π，2,4]崎二 唑-5-基]-吡啶係使用通用程序D，自3•氯羥基異丙氧 基-苯曱脒製備，如下列合成反應圖中所示：General Procedures List of General Procedures A: Preparation of 4-Phenoxy Groups Using Triphenylphosphine _ Section General Procedure B: Use of Triphenylphosphine Dibenzonitrile in Combination with Polymers General Procedure C: General Procedure for Preparation of Hydroxylhydrazine D: General procedure for the formation of oxadiazole from acid E: General procedure for the formation of oxadiazole from helium: F: Formation of helium from acid 127788.doc • 82- 200840567 General procedure G: Self-guessing the general procedure for the formation of Η: Amine of aldehyde General Procedures for I: Generalization of Iridylation with Acrylate General Procedure J: General Procedure for Dealkylation with Bromide 去: Deprotection of Third Butyl Ester General Procedure L: General Procedure for Amination of Aromatic Halides Μ: Hyunji indifferent Mitsonubu reaction General procedure N: Debenzylation general procedure Ο: Protected I, 2-diol deprotection General procedure application example The general program letter code constitutes the synthetic route of the final product. A practical example of how to determine a path is provided below using Example A33 as a non-limiting description. Example A33, 4-[3·(3-oxaisopropoxy)phenyl]-π,2,4]soxadiazol-5-yl]-pyridine was synthesized using the general procedure D from 3 • chlorohydroxyisopropoxy The base-benzoquinone is prepared as shown in the following synthesis scheme:

貝例Α33之鈾驅物，3 -氯-Ν·羥基-4-異丙氧基-苯甲脒係 使用路徑(A、C)製備。此可轉換成下列合成順序，其中通 用私序D中使用之羥基曱脒起始物質為藉下列程序a及c， 依既定順序製造之產物： 127788.doc -83 - 200840567The uranium drive of the sample Α33, 3-chloro-indole hydroxy-4-isopropoxy-benzamide is prepared using the route (A, C). This can be converted into the following synthetic sequence, wherein the hydroxy hydrazine starting material used in the private sequence D is a product manufactured in the following order by the following procedures a and c: 127788.doc -83 - 200840567

(A)(A)

(C)(C)

OHOH

通用程序A :使用=贫I 之用一本基膦製備4-烧氧基节腈 在氣氣下將三笨基膦（去 田里車父好I·6當量）及4絲苴 苄腈（較好1當量）溶於A7k 士 里）及4-羥基- 、.、、、水有機溶劑如二氯曱烷、General Procedure A: Preparation of 4-oxooxynitrile with a base phosphine using a base phosphine, trisylphosphine (1 to 6 equivalents) and 4-filamented benzonitrile (under the air) Preferably 1 equivalent) is dissolved in A7k, and 4-hydroxy-, ., ,, water, organic solvents such as dichloromethane,

氫呋喃（較好為四氫呋喃）中 本或四 _ , ^ ^ 間早攪捽後’將偶氮二曱酸 δ曰如偶氮二甲酸二乙酯、？ 一 偶虱一曱酸二異丙酯或偶氮二甲 酸二第三丁酯（較好為俚…一甲 曰(季又好為偶虱二曱酸二第三丁醋)(1_3當量， 車父好u當量）添加於溶液中且使混合賴掉數分鐘接著 添加無水乙醇（1_3當量，較好125當量）。使反應混合物在 〇士-i〇〇c(較好約23。〇下及氮氣中攪拌約2_24小時（較好16小 時）。減壓移除溶劑。粗製產物經快速管柱層析進一步純 化。 ' 通用程序A之舉例·· 3-氣-4-異丙氧基-苄腈之製備In hydrogen furan (preferably tetrahydrofuran), after mixing with _, ^ ^, and then argon dicarboxylic acid δ such as diethyl azodicarboxylate, ? Iso-diisopropyl isopropylate or di-tert-butyl azodicarboxylate (preferably 俚...one formazan (season is good for diterpene diacetate, third butyl vinegar) (1_3 equivalent, car The parent is preferably added to the solution and the mixture is allowed to stand for a few minutes followed by the addition of absolute ethanol (1 - 3 equivalents, preferably 125 equivalents). The reaction mixture is made in a gentleman-i〇〇c (preferably about 23. Stirring under nitrogen for about 2-24 hours (preferably 16 hours). The solvent is removed under reduced pressure. The crude product is further purified by flash column chromatography. ' General procedure A. · 3- 3--4-isopropoxy-benzyl Preparation of nitrile

於含三苯基膦（27.3克，104毫莫耳）及3_氯·4_羥基_节腈 (10克’ 65耄莫耳）之圓底瓶中添加無水四氫π夫喃（⑼〇 a 升）°使混合物在氮氣中簡單攪拌，接著添加偶氮二甲酸 二第三丁酯（24克，104毫莫耳）。使混合物攪拌數分鐘，接 -84- 127788.doc 200840567 著添加無水異丙醇（6.23毫升，814毫莫耳）。使反應混合 物在室溫下及ll氣中授拌隔夜。使粗製產物經快速層析， 使用1:4(WV)乙酸乙醋/庚烷作為溶離液純化。溶離液經乾 烯獲知紅-橙色半固體之3_氯_4_異丙氧基_苄腈（122克， 91%)。 LCMS(表 1，方法d) Rt=2.36 min，m/z 152 i (Μ+Η)+; ιΗ NMR (400 MHz，DMSO〇 δ 7·74 (d，1H)，7·61 (dd，1H)， 7.14 (d，1H)，4.75 (sept·，1H)，1.34 (d，6H)。 通用程序B ·使用與聚合物結合之三苯基膦製備4烷氧基· 苄腈 於溶於適宜溶劑如二氣甲烷、二氯乙烷、四氫呋喃或 1，4-二噚烷（較好為四氫呋喃）之醇（較好丨當量）及‘羥基_苄 腈（較好1 i里）中添加與聚合物結合之三苯基膦（1 當量， 較好2當置）及偶氮二甲酸酯如偶氮二甲酸二乙酯、偶氮二 曱酸一異丙酯或偶氮二曱酸二第三丁酯（較好為偶氮二甲 酸二異丙酯）（1-2當量，較好為15當量）。使混合物在約ο-ΐ 〇〇°C (較好約 23 °C ) 下搖晃 4-24 小時 （較好 丨 6 小時 ） 。 粗製混 合物經過濾且以適宜溶劑如二氣甲烷、二氣乙烷、四氫呋 喃或1，4-二唠烷（較好為四氫呋喃）洗滌樹脂。減壓濃縮濾 液至乾，且使殘留物進行通用程序C。 通用程序B之舉例： 3-氣-4-(1-乙基-丙氧基）_苄腈之製備Adding anhydrous tetrahydropyrene ((9)〇 to a round bottom flask containing triphenylphosphine (27.3 g, 104 mmol) and 3-chloro-4-hydroxyl-n-nitrile (10 g '65 Torr) a liter) ° The mixture was simply stirred under nitrogen, followed by the addition of di-t-butyl azodicarboxylate (24 g, 104 mmol). The mixture was stirred for a few minutes, and anhydrous isopropyl alcohol (6.23 mL, 814 mmol) was added to -84-127788.doc 200840567. The reaction mixture was allowed to stand overnight at room temperature and in ll. The crude product was purified by flash chromatography using 1 : 4 (WV) ethyl acetate / heptane as eluent. The eluate was obtained as a red-orange semisolid 3-chloro-4-isopropoxy-benzonitrile (122 g, 91%). LCMS (Table 1, Method d) Rt = 2.36 min, m/z 152 i (Μ+Η)+; ιΗ NMR (400 MHz, DMSO 〇 δ 7.74 (d, 1H), 7.61 (dd, 1H) ), 7.14 (d,1H), 4.75 (sept·,1H), 1.34 (d,6H). General procedure B. Preparation of 4-alkoxy·benzonitrile using triphenylphosphine in combination with polymer A solvent such as di-methane, dichloroethane, tetrahydrofuran or 1,4-dioxane (preferably tetrahydrofuran) alcohol (preferably equivalent) and 'hydroxy-benzonitrile (preferably 1 i) are added and a polymer-bound triphenylphosphine (1 equivalent, preferably 2) and an azodicarboxylate such as diethyl azodicarboxylate, monoisopropyl azodicarboxylate or azobisphthalic acid a third butyl ester (preferably diisopropyl azodicarboxylate) (1-2 equivalents, preferably 15 equivalents). The mixture is allowed to be at about ο-ΐ 〇〇 ° C (preferably about 23 ° C). Shake for 4-24 hours (preferably 丨 6 hours). The crude mixture is filtered and washed with a suitable solvent such as di-methane, di-hexane, tetrahydrofuran or 1,4-dioxane (preferably tetrahydrofuran). Concentrate the filtrate to dryness and make the residue General procedure C. Example of general procedure B: Preparation of 3-gas-4-(1-ethyl-propoxy)-benzonitrile

127788.doc 200840567 於含有溶於THF(2毫升）之戊_3_醇（22毫克，〇·25毫莫耳） /谷液之閃爍藥瓶中添加含3_氯_4_經基_苄腈（38毫克， 笔莫耳）之THF(2毫升）溶液，接著添加ps_pph3樹脂（357毫 克，0.5¾莫耳，負荷14毫莫耳/克）及含diad(76毫克， 0.375毛莫耳）之THF(2t升）溶液。蓋住藥瓶且在室溫下搖 晃隔仪。反應混合物經過濾且以THF(4毫升）洗滌樹脂。濃 縮濾液至乾，獲得3-氣_4_(1_乙基_丙氧基）_苄腈。 通用程序C:羥基甲脒之製備 於含苄腈（1當量）之適宜溶劑如甲醇、乙醇、異丙醇或 水（較好為乙醇）之溶液中添加（i_5()當量，較好為當 罝）。使反應混合物在約25-100。(：（較好60。(：）下加熱約2-24 小時（較好1 6小時）。減壓移除溶劑。使粗製產物經真空乾 燥，且在進行通用程序D或E。 通用程序C之舉例： 3-氣-N·羥基_4_異丙氧基_苯曱脒之製備127788.doc 200840567 Adding 3-Chloro-4-yl-based-benzylic acid to a scintillation vial containing pent-3-ol (22 mg, 〇·25 mmol) / gluten solution in THF (2 ml) A solution of nitrile (38 mg, penmo) in THF (2 mL), followed by ps_pph3 resin (357 mg, 0.53⁄4 mol, load 14 mmol/g) and containing diad (76 mg, 0.375 mmol) THF (2 t liter) solution. Cover the vial and shake the separator at room temperature. The reaction mixture was filtered and washed with EtOAc EtOAc. The filtrate was concentrated to dryness to give 3- gas_4_(1-ethyl-propoxy)-benzonitrile. General procedure C: Preparation of hydroxyformamidine is added to a solution of a suitable solvent such as methanol, ethanol, isopropanol or water (preferably ethanol) containing benzonitrile (1 equivalent) (i_5() equivalent, preferably when罝). The reaction mixture is allowed to be between about 25 and about 100. (: (better 60. (:)) heating for about 2-24 hours (preferably 16 hours). The solvent is removed under reduced pressure. The crude product is dried in vacuo and subjected to the general procedure D or E. An example of the preparation of 3-gas-N·hydroxy- 4_isopropoxy-benzoquinone

ΗοΝ-0Η 乙醇ΗοΝ-0Η ethanol

於圓底瓶中添加3-氯-4-異丙氧基-节腈（5.00克，25.6毫 莫耳）、羥基胺（50重量％於水中，ι·86毫升，28.1毫莫耳） 及乙醇（150毫升）。使混合物在約6(rc下加熱隔夜。反應完 全後’減壓濃縮混合物至乾，獲得淡黃色固體之3_氯 經基-4-異丙氧基-苯曱脒（5.76克，94%)。Add 3-chloro-4-isopropoxy-quinone (5.00 g, 25.6 mmol), hydroxylamine (50 wt% in water, ι·86 ml, 28.1 mmol) and ethanol to a round bottom flask. (150 ml). The mixture was heated at about 6 (rc. EtOAc). EtOAc was evaporated. .

LCMS(表 1，方法a) Rt=2 〇9 min，m/z 229 (M+H)+; NMR 127788.doc -86- 200840567 (400 MHz，DMSO〇 δ 9 58 (s，1H)，7 7() (d，1H)，7 59 ⑽， 1H)，7·15 (d，1H)，5.81 (s，2H)5 4·69 (七重峰，1H)，1.29 (d， 6H) 〇LCMS (Table 1, Method a) Rt = 2 〇 9 min, m/z 229 (M+H)+; NMR 127788.doc -86 - 200840567 (400 MHz, DMSO 〇 δ 9 58 (s, 1H), 7 7() (d,1H),7 59 (10), 1H),7·15 (d,1H),5.81 (s,2H)5 4·69 (seven peaks, 1H), 1.29 (d, 6H) 〇

通用程序D:自酸形成〃号二嗓 於反應瓶中添加羥基甲脒（〇 9-15當量，較好hl當量）及 酉文（〇·9一1,5备里’較好1當量）、偶合試劑如HBTU、 HATU、HOBt或與聚合物結合之恥叫較好為hob^之當 里，較好1當置）、碳二醯亞胺如EDCI、DIC、Dcc或與聚 e物、、、σ a iDCC(車乂好為與聚合物結合之Dec)。當量， 三乙胺或Ν-曱基嗎啉 較好3當量）、驗如General procedure D: Adding hydroxyformamidine (〇9-15 equivalents, preferably hl equivalent) to the reaction flask from the acid formation 嗓2嗓 and 酉文(〇·9-1,5 备里' preferably 1 equivalent) The coupling reagent such as HBTU, HATU, HOBt or the combination with the polymer is preferably in the case of hob^, preferably 1), carbodiimide such as EDCI, DIC, Dcc or with polye, , σ a iDCC (the rut is good for the polymer combined with Dec). Equivalent, triethylamine or hydrazine-hydrazinomorpholine is preferably 3 equivalents)

(較好為二異丙基胺)(1·3當量’較好3當量)及適宜之溶劑 如膽、DMA或乙腈（較好為乙腈）。將反應瓶蓋住且在 1〇〇-2〇代（較好16G°C)下加熱（習知加熱或微波加熱，較好 為微波加熱）歷時15_45分鐘（較好30分鐘）。冷卻至室溫 後’過濾粗製反應混合物’以適宜溶劑如dmf、DMA或乙 腈(較好為乙腈)洗蘇’且減壓濃縮渡液至乾。使粗製產物 經層析進一步純化。 通用程序D之舉例·· 4-[3-(3-氣-4-異丙氧基-笨基) 吡啶之製備 二唑-5-基卜3_甲基-(preferably diisopropylamine) (1.3 equivalents, preferably 3 equivalents) and a suitable solvent such as biliary, DMA or acetonitrile (preferably acetonitrile). The reaction flask is capped and heated at 1 〇〇 to 2 ( (preferably 16 G ° C) (conventional heating or microwave heating, preferably microwave heating) for 15 to 45 minutes (preferably 30 minutes). After cooling to room temperature, the crude reaction mixture is filtered and washed with a suitable solvent such as dmf, DMA or acetonitrile (preferably acetonitrile) and the mixture is concentrated to dryness under reduced pressure. The crude product was further purified by chromatography. An example of the general procedure D·· Preparation of 4-[3-(3- gas-4-isopropoxy-phenyl)pyridine Diazole-5-ylbu-3_methyl-

++

HOHO

HOBt, PS-DCC DIEAHOBt, PS-DCC DIEA

於 饋入有3_氣喜經基+異丙氧基·笨甲脒、(75毫克， 127788.doc -87- 200840567 0.328¾莫耳）、3 -甲基-異於驗酸（41毫克，〇 29 8毫莫耳）、 HOBt(46毫克，〇,298毫莫耳）、PS-碳二醯亞胺（720毫克， 0.894毫莫耳，負荷1.24毫莫耳/克）之微波瓶中添加乙腈 (3·5毫升）及二異丙基乙胺（156微升，〇 894毫莫耳）。將反 應瓶蓋住且在Biotage微波中約160°C下加熱約30分鐘。過 濾反應混合物且以乙腈（4毫升）洗滌該樹脂。濃縮濾液至 乾。使粗製產物經逆相HPLC(30-90%乙腈，30分鐘遞增） 純化，獲得10.2毫克（10%)之4-[3-(3-氯_本異丙氧基-笨基）_ [1，2,4]嘮二唑-5-基]-3-甲基·吡啶。In the feed, there are 3_ gas oxime + isopropoxy oxymethyl, (75 mg, 127788.doc -87-200840567 0.3283⁄4 mol), 3-methyl-iso-acid (41 mg, 〇29 8 mM), HOBt (46 mg, 〇, 298 mmol), PS-carbodiimide (720 mg, 0.894 mmol, load 1.24 mmol/g) in a microwave vial Acetonitrile (3.5 ml) and diisopropylethylamine (156 microliters, 〇894 mm). The reaction flask was capped and heated at about 160 ° C in a Biotage microwave for about 30 minutes. The reaction mixture was filtered and washed with EtOAc (4 mL). The filtrate was concentrated to dryness. The crude product was purified by reverse phase HPLC (30-90% acetonitrile, 30 min) to afford 10.2 g (10%) of 4-[3-(3-chloro-propenyloxy-phenyl). , 2,4]oxadiazol-5-yl]-3-methylpyridine.

LCMS(表 1，方法c) Rt=2.70 min，330 (M+H)+;NMR (400 MHz，DMSOO δ 8·77 (s，1H)，8·69 (d，1H)，8·06 (d， 1H)，8.01 (dd，2H)，7·39 (d，1H)，4.83 (sept·，1H)，2 70 (s 3H)，1.35 (d，6H)。 通用程序E:自醯氣形成噚二唑 於含3-氯羥基-4-烷氧基-苯甲脒（較好1當量）之吡啶溶 液中添加含醯氯（1-3當量，較好2當量）之吡啶溶液。使反 應混合物在60-10(TC(較好10(TC)下加熱8_24小時（較好加小 時）。減壓移除溶劑且使殘留物經層析進一步純化。 通用程序E之舉例： 3-【3-氣-4-(1·乙基-丙氧基）_苯基】_5_鄰-甲苯基丨124】哼二 唑之製備 ’LCMS (Table 1, Method c) Rt = 2.70 min, 330 (M+H)+; NMR (400 MHz, DMSOO δ 8·77 (s, 1H), 8.69 (d, 1H), 8·06 ( d, 1H), 8.01 (dd, 2H), 7.39 (d, 1H), 4.83 (sept·, 1H), 2 70 (s 3H), 1.35 (d, 6H). General procedure E: self-helium To form a pyridine solution containing ruthenium chloride (1-3 equivalents, preferably 2 equivalents) in a pyridine solution containing 3-chlorohydroxy-4-alkoxy-benzamide (preferably 1 equivalent). The reaction mixture is heated at 60-10 (TC (preferably 10 (TC) for 8-24 hours (preferably plus hours). The solvent is removed under reduced pressure and the residue is further purified by chromatography. Example of General Procedure E: 3- [ Preparation of 3-ox-4-(1·ethyl-propoxy)-phenyl]_5_o-tolylhydrazin 124]oxadiazole

127788.doc -88 - 200840567 於含3-氯-4-(1-乙基-丙氧基）_N_經基_苯甲脉⑹ 〇·25毫莫耳）（以通用程序B製備）之㈣〇毫升）溶液中& 含2-甲基苯甲醯氯（77毫克，〇 5蒼莖耳、夕， 毛莫耳）之吡啶（1毫升）滚 液。使混合物在約赋下加熱隔夜。減壓移除溶劑且 粗製產物經SFC純化（C〇2〇4Me〇H ,梯度5%維持〇5八 鐘’自7.3%遞增至50%歷時6.5分鐘，維持在5〇%歷時^ 鐘），獲得3-[3_氯·4_(1•乙基_丙氧基）_苯基]_5•鄰-甲笨基刀· [1，2,4]吟二唑（16.5毫克，18·5〇/〇)。 土127788.doc -88 - 200840567 (4) in the presence of 3-chloro-4-(1-ethyl-propoxy)-N-carbyl-benzoyl (6) 〇·25 mmol (prepared by General Procedure B) 〇ml) solution & pyridine (1 ml) containing 2-methylbenzamide chloride (77 mg, 〇5 stalk ear, eve, hair molar). The mixture was allowed to heat overnight. The solvent was removed under reduced pressure and the crude product was purified by SFC (C 〇 2 〇 4Me 〇H, gradient 5% 〇 〇 八 八 ' ' ' 7.3 7.3 7.3 7.3 7.3 7.3 7.3 7.3 7.3 7.3 7.3 7.3 6.5 6.5 6.5 6.5 , , , , , , , , , , , , , , , Obtained 3-[3_chloro.4_(1•ethyl-propoxy)-phenyl]_5•o-methyl-based knives·[1,2,4]oxadiazole (16.5 mg, 18·5〇) /〇). earth

LCMS (表 1，方法b) Rt=3.18 min，m/z 356.13 (Μ-Η)' ιΗ NMR (400 MHz, CHCls) δ 8.19 (d, 1H), 8.16 (dd, 1H), 8.〇l (dd，1H)，7.48 (m, 1H)，7.37 (d，1H), 7.01 (d，1H)，4.28 (m 1H)，1·77 (m，4H)，1.01 (t，6H)。 ’ 3-(3-氣·4-異丙氧基苯基比啶_4-基卜丨^^呤二唑 之製備LCMS (Table 1, Method b) Rt=3.18 min, m/z 356.13 (Μ-Η)' ιΗ NMR (400 MHz, CHCls) δ 8.19 (d, 1H), 8.16 (dd, 1H), 8.〇l (dd, 1H), 7.48 (m, 1H), 7.37 (d, 1H), 7.01 (d, 1H), 4.28 (m 1H), 1 · 77 (m, 4H), 1.01 (t, 6H). Preparation of 3-(3- gas·4-isopropoxyphenylpyridinyl-4-isobupyridinium oxadiazole

於含3-氯異終驗醯氣（約2.6毫莫耳）（以通用程序F製備）之 吼淀（5毫升）溶液中添加3-氣-4-異丙氧基-N-羥基-苯甲脉 (3〇〇毫克，1.31毫莫耳）（以通用程序B製備）。使混合物在 1 〇〇°C下加熱隔夜。減壓移除溶劑且使粗製產物經正相石夕 膠層析（0-50%乙酸乙酯/庚烷梯度歷時30分鐘）純化，獲得 3-(3-氯-4-異丙氧基苯基）-5-(3-氯吼啶-4-基）-[1，2,4]-崎二唑 (323毫克，70.3%)。 127788.doc -89- 200840567 LCMS(表 1，方法b) Rt=3.88 min，m/z 349.04Add 3-ox-4-isopropoxy-N-hydroxy-benzene to a solution of 3-chloroiso-injected helium (about 2.6 mmol) (prepared by General Procedure F) in a solution (5 ml) A pulse (3 mg, 1.31 mmol) (prepared by General Procedure B). The mixture was heated overnight at 1 °C. The solvent was removed under reduced pressure and the crude material was purified eluting with EtOAc EtOAc EtOAc EtOAc 5-(3-chloroacridin-4-yl)-[1,2,4]-soxadiazole (323 mg, 70.3%). 127788.doc -89- 200840567 LCMS (Table 1, Method b) Rt = 3.88 min, m/z 349.04

NMR (400 MHz，CHC13)=8.84 (d，1H)，8.69 (d，1H)，8.U (d，1H)，8.02 (d，1H)，7.99 (dd，1H)，7·02,（d5 1H)，4.69 (m， 1H)，1·44 (d，6H)。 通用程序F:自酸形成醯氣NMR (400 MHz, CHC13) = 8.84 (d, 1H), 8.69 (d, 1H), 8.U (d, 1H), 8.02 (d, 1H), 7.99 (dd, 1H), 7·02, ( D5 1H), 4.69 (m, 1H), 1.44 (d, 6H). General procedure F: Formation of helium from acid

於含酸（較好1當量）之適宜溶劑如二氣甲烷、二氯乙烷 (車父好為二氯曱烷）中添加氣化劑如亞硫醯氯、草醯氯（較好 為亞硫醯氣）（1-100當量，較好3當量）。使反應混合物在 (較好約23°〇下擾拌1-24小時（較好3小時）。減壓移 除溶劑。真空乾燥粗製產物且接著進行通用程序E。 通用程序F之舉例： 3·甲基-異於驗醯氯之製備Adding a gasifying agent such as sulfinium chloride or oxalic acid chloride to a suitable solvent containing acid (preferably 1 equivalent) such as di-methane or dichloroethane (the car is preferably dichloromethane) (preferably sub- Thiopurine) (1-100 equivalents, preferably 3 equivalents). The reaction mixture is allowed to scramble for 1 to 24 hours (preferably 3 hours) at a temperature of about 23 ° C. The solvent is removed under reduced pressure. The crude product is dried in vacuo and then subjected to the general procedure E. Example of General Procedure F: Methyl-different from the preparation of chlorine

soci2Soci2

DCM 於懸浮在DC Μ (2· 5毫升）中夕q田甘 # ^ )〒之3-甲基異於驗酸（1〇〇毫克， 0.729¾莫耳）中添加亞硫 爪恥虱（260耄克，2.188毫莫耳）。使 反應混合物在室溫下播姓 I拌、、々3小呀。減壓移除溶劑且使殘 留物經高度真空乾燥1小 ^ 獲付3 -甲基-異於驗醯氣。 甲基-異菸鹼醯氣之製備 HO\/〇DCM was suspended in DC Μ (2.5 ml) in the middle of the q tiangan # ^ ) 〒 3-methyl iso-acid test (1 〇〇 mg, 0.7 293⁄4 mol) added sulfite claw shame (260 Mike, 2.188 millimoles). The reaction mixture was soaked at room temperature, and the mixture was simmered for 3 hours. The solvent was removed under reduced pressure and the residue was dried under high vacuum for 1 y. Preparation of methyl-isonicotinine helium HO\/〇

Cl S〇CI2 NCl S〇CI2 N

DCM CI\/〇DCM CI\/〇

Cl 於3 -氣異於驗酸（q I]毫克， 2.62毫莫耳）中 添加亞硫酸氯 127788.doc 200840567 7毫升，68.5毫莫耳）。使反應混合物在室溫下攪拌約汕小 知。減壓濃縮溶液且使殘留物經高度真空乾燥丨小時，獲 传3 -氣·異於驗酸氯。 通用程序G:自腈形成醛 使在圓底瓶中之含腈（0.9-L2當量，較好1〇當量）之適宜 溶劑如二氯甲烷或二氯乙烷（較好為二氯甲烷）之混合物冷 卻至（TC至-60°C之間（較好_4〇。〇。滴加DIBAL(0.9-2.5當 量，較好2.0當量）且接著攪拌15_45分鐘（較好3〇分鐘），以 甲醇終止反應，升溫至周圍溫度且以1〇% R〇cheUets鹽溶 液處理。以DCM萃取後使合併之有機層與稀酸水溶液（較 好1 M HC1水溶液）攪拌。使層分離且以dCM萃取水層。合 併之有機層以鹽水洗滌，以MgS〇44Na2S〇4脫水，經過濾 且蒸發至乾。使粗製產物經層析進一步純化。 通用程序G之舉例： 3-氣-4-(3-(3-氣-4-異丙氧基苯基）4,2,4-噚二唑-5·基）苄腈 之製備Cl was added to 3-acid as a test acid (q I) mg, 2.62 mmol. Add chlorosulfite 127788.doc 200840567 7 ml, 68.5 mmol. The reaction mixture was stirred at room temperature for about a few minutes. The solution was concentrated under reduced pressure and the residue was dried under high vacuum for </ RTI> hrs. General Procedure G: Forming an aldehyde from a nitrile such that a suitable solvent such as dichloromethane or dichloroethane (preferably dichloromethane) is present in the round bottom flask containing nitrile (0.9-L2 equivalent, preferably 1 equivalent). The mixture is cooled to between (TC and -60 ° C (preferably _4 Torr. 〇. DIBAL (0.9-2.5 equivalents, preferably 2.0 equivalents) is added dropwise and then stirred for 15 - 45 minutes (preferably 3 Torr) with methanol The reaction was terminated, warmed to ambient temperature and treated with 1% R〇cheUets salt solution. After extraction with DCM, the combined organic layers were stirred with a dilute aqueous acid solution (preferably 1 M aqueous HCl). The combined organic layers were washed with brine, dried with EtOAc EtOAc EtOAc EtOAc EtOAc. Preparation of 3-oxo-4-isopropoxyphenyl) 4,2,4-oxadiazol-5-yl)benzonitrile

於100毫升裝置配備有氮氣輸入針頭之隔離蓋之RBF中 饋入含3 -氣-4-(3-(3 -氯-4-異丙氧基苯基）-1，2，4-4二哇- 5-基）苄腈（1.529克，3_27毫莫耳）之DCM(65.4毫升)，獲得橘 色溶液。經乙腈-乾冰浴使反應混合物冷卻至約-40°C。接 著在約_4〇°C下滴加DIBAL_H(3.6〇毫升，3·60毫莫耳）。使 127788.doc -91 - 200840567 所得混合物在約_40°C下攪拌約2小時。接著在約_40°C下於 反應混合物中滴加甲醇（〇,5毫升，12.36毫莫耳）。移開冰 /谷且使反應升溫至周圍溫度’接著添加鹽溶液 (60毫升）。使所得混合物劇烈攪拌3小時。分離水層。有機 相以鹽水洗滌，經脫水（MgSCU)且濃縮，獲得粗製黃色 油。使殘留物經Analogix FC系統，使用Redisep RS I20g 官柱，以（M5% EtOAc/庚烷梯度在40毫升/分鐘下歷時4〇 分鐘’接著保持在15%直到所有峰均溶離而純化。合併含 產物之溶離份且濃縮，獲得3-氯-4_(3-(3_氯_4•異丙氧基苯 基）-1，2,4_噚二唑-5-基）苄腈（0.791克，2.09毫莫耳）。4 圓R (400 MHz，CZ)C/3) δ ppm ΐ〇·〇9 (s，1H)，8 35 (d， J=8,02 Hz，1H)，8.21 (d，J=1.90 Hz，1H)，8·09 (s，1Η)，8·03 (dd，J二8·56, 1·86 Hz，1H)，7.94 (dd，J=8.04, 〇·79 Hz，1H)， 7.05 (d，J = 8.62 Hz，1H)，4.69 (td，J=12.05, 6.04 Hz，1H)， 1.45 (t, J=6.80 Hz5 6H) 〇 通用程序H:醛之胺化作用 使含胺（0.9-1 ·2當量，較好hl當量）、醛（o n 2當量， 較好1.G當量）、適㈣原劑如聚合物支#之氰基贱化納 或氰基硼氫化鈉（較好為聚合物支撐之氰基硼氫化鈉）（15_ 3.0當量，較好為2.0當量）、乙酸（2_24滴，較好响及適宜 溶劑如DCM或甲醇（較好為DCM)之混合物在周圍溫度下攪 拌4·72小時，較好24小時。使粗製產物經層析進一步純 化。 通用程序Η之舉例： 127788.doc -92- 200840567 1·(3 -氣-4-(3-(3_氣-4-異丙氧基苯基）-1，2,4_吟二唾_5-基）节 基）_3_甲基吖丁啶-3-曱酸之製備Feeding 3-fluoro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-4 in RBF in a 100 ml device equipped with a nitrogen inlet needle isolation cover Wow- 5-yl)benzonitrile (1.529 g, 3-27 mmol) in DCM (65.4 mL). The reaction mixture was cooled to about -40 ° C in an acetonitrile-dry ice bath. Then, DIBAL_H (3.6 ml, 3.60 mmol) was added dropwise at about _4 °C. The resulting mixture was stirred at about _40 ° C for about 2 hours. Methanol (〇, 5 ml, 12.36 mmol) was then added dropwise to the reaction mixture at about _40 °C. The ice/valley was removed and the reaction was allowed to warm to ambient temperature&apos; followed by the addition of a salt solution (60 mL). The resulting mixture was stirred vigorously for 3 hours. Separate the water layer. The organic phase was washed with brine, dried (MgSO.sub.) and concentrated to afford crude crude oil. The residue was purified by an Analogix FC system using a Redisep RS I20g column eluting with a gradient of M.sub.5 EtOAc/Heptane (40 mins. The product was dissolved and concentrated to give 3-chloro-4_(3-(3_chloro-4)isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (0.791 g) , 2.09 millimoles). 4 circle R (400 MHz, CZ) C/3) δ ppm ΐ〇·〇9 (s, 1H), 8 35 (d, J=8,02 Hz, 1H), 8.21 ( d, J=1.90 Hz, 1H), 8·09 (s, 1Η), 8·03 (dd, J 2·8·56, 1·86 Hz, 1H), 7.94 (dd, J=8.04, 〇·79 Hz, 1H), 7.05 (d, J = 8.62 Hz, 1H), 4.69 (td, J = 12.05, 6.04 Hz, 1H), 1.45 (t, J = 6.80 Hz5 6H) 〇General procedure H: Amination of aldehyde The action is to make an amine (0.9-1 · 2 equivalents, preferably hl equivalent), an aldehyde (on 2 equivalents, preferably 1. G equivalents), a suitable (tetra) starting agent such as a polymer branch of cyanoguanidine or a cyano group. Sodium borohydride (preferably polymer supported sodium cyanoborohydride) (15-3.0 equivalents, preferably 2.0 equivalents), acetic acid (2-24 drops, preferably in a suitable solvent such as DCM or methanol) The mixture, preferably DCM), is stirred at ambient temperature for 4.72 hours, preferably 24 hours. The crude product is further purified by chromatography. General procedure Η Example: 127788.doc -92- 200840567 1·(3 - gas - 4-(3-(3_Gas-4-isopropoxyphenyl)-1,2,4-indole di-salt-5-yl)]-3-methylazetidine-3-decanoic acid preparation

於5 00宅升RBF中饋入3 -氣-4-(3-(3 -氣-4-異丙氧基苯基）_ 1，2,4_噚二唑-5-基）苯甲醛(;0.745克，1.975毫莫耳）、3_甲基 °丫丁咬甲酸乙酯（0.566克，3.95毫莫耳 Zeiier 1991, 32, 36，4795479S)及甲醇（197毫升）。於其中 添加乙酸（0.904毫升，15.80毫莫耳）。使所得混合物在周 圍溫度下攪拌約1小時，接著一次添加氰基硼氫化鈉（〇.〇95 克，1·512毫莫耳）。使反應在周圍溫度下攪拌約17小時。 以LCMS監控反應過程。真空濃縮反應，獲得粗製深黃色 油。使殘留物經Analogix FCC系統純化，使用120克Redi-Sep管柱，在50毫升/分鐘下，梯度為〇_4〇% m〇Ac/庚烷歷 時45分鐘，接著維持在4〇% Et0Ac下直到所有峰均溶離為 止而純化。合併含產物之溶離份並經濃縮，獲得〇·82〇克 (1.626¾莫耳）之無色油。使該物質溶於tHF(8〇毫升）中。 於其中添加NaOH(9·0毫升，9.00毫莫耳）之lN溶液，接著 添加MeOH(約25毫升）。使反應在周圍溫度下攪拌約3小 時，隨後經LCMS顯示已完全水解。於反應混合物中滴加 HC1(9.0毫升’ 9·00毫莫耳⑷N溶液使pH中和。真空濃縮 反應混合物再經凍乾。使粗製白色固體研散於二乙醚及 DCM中過;慮。所得固體以大量水洗开条，再、經供箱乾燥 127788.doc -93· 200840567 隔夜，獲得白色固體之1-(3-氯-4-(3-(3-氯-4-異丙氧基苯 基）-1，2,4-嘮二唑-5-基）苄基）-3-曱基吖丁啶-3-甲酸（0.377 克，0.75毫莫耳）。LCMS(表 1，方法 a) Rt=1.81 min.; MS m/z: 476.15 (Μ+Η)^.^ NMR (400 MHz5 DMSO) δ ppm 12.67-12.25 (m，1H)，8.24-7.93 (m，3H)，7.73-7.32 (m，3H)， 4.90-4.76 (m，1H)，3.69 (s，2H)，3.43 (d，J = 6.51 Hz，2H)， 3·09 (d，J=6.43 Hz，2H)，1·45 (s，3H)，1.35 (d，J=5.75 Hz， 6H)。 通用程序I :以丙烯酸酯使吲哚烷化 在60°C下於含吲哚（ο.、〗.]當量，較好ι 〇當量）之適宜溶 劑如乙腈溶液中添加丙烯酸酯（丨·〇_2·〇當量，較好1.5當量） 及鹼如DBU(0.3-1.0當量，較好0·5當量）。使混合物在約 5〇°C下攪拌隔夜。減壓移除溶劑且使粗製產物溶於dcM 中’以鹽水洗滌，以MgS〇4或Na2S04脫水，經過濾且減壓 移除溶劑。使粗製產物經層析或再結晶進一步純化。 通用程序I之舉例： 3-(4_(3-(3-氣-4-異丙氧基苯基）β1，2,4 _噚二唑基）_1H吲 哚-1-基）丙酸第三丁酯之製備Feeding 3 - gas-4-(3-(3- gas-4-isopropoxyphenyl)-1 1,2,4-oxadiazol-5-yl)benzaldehyde in 500 liters of RBF ; 0.745 g, 1.975 mmol; 3, methyl butyl ethyl benzoate (0.566 g, 3.95 mmol, Zeiier 1991, 32, 36, 4795479) and methanol (197 ml). Acetic acid (0.904 ml, 15.80 mmol) was added thereto. The resulting mixture was stirred at ambient temperature for about 1 hour, followed by the addition of sodium cyanoborohydride (95 g, 1.512 mmol). The reaction was allowed to stir at ambient temperature for about 17 hours. The reaction process was monitored by LCMS. The reaction was concentrated in vacuo to give a crude dark yellow oil. The residue was purified on an Analogix FCC system using a 120 gram Redi-Sep column at 50 mL/min with a gradient of 〇_4〇% m〇Ac/heptane for 45 minutes, then maintained at 4〇% Et0Ac Purification was continued until all peaks were dissolved. The product-containing fractions were combined and concentrated to give a colorless oil of &lt;RTI ID=0.0&gt; This material was dissolved in tHF (8 mL). A 1N solution of NaOH (9.0 mL, 9.00 mmol) was added thereto, followed by MeOH (about 25 mL). The reaction was allowed to stir at ambient temperature for about 3 hours and then showed complete hydrolysis by LCMS. The reaction mixture was added dropwise HCl (9.0 ml of a 9.0 mmol/m) solution to neutralize the pH. The reaction mixture was concentrated in vacuo and lyophilized. The crude white solid was crystallized in diethyl ether and DCM; The solid was washed with a large amount of water, and then dried in a box 127788.doc -93·200840567 overnight to obtain 1-(3-chloro-4-(3-(3-chloro-4-isopropoxybenzene) as a white solid. -1,2,4-oxadiazol-5-yl)benzyl)-3-indolylpyridin-3-carboxylic acid (0.377 g, 0.75 mmol). LCMS (Table 1, Method a) Rt=1.81 min.; MS m/z: 476.15 (Μ+Η)^.^ NMR (400 MHz5 DMSO) δ ppm 12.67-12.25 (m,1H), 8.24-7.93 (m,3H), 7.73-7.32 ( m,3H), 4.90-4.76 (m,1H), 3.69 (s,2H), 3.43 (d,J = 6.51 Hz, 2H), 3·09 (d, J=6.43 Hz, 2H),1·45 (s, 3H), 1.35 (d, J = 5.75 Hz, 6H). General procedure I: decylation with acrylate at 60 ° C in 吲哚 (ο., 〖.) equivalent, preferably A suitable solvent such as ι 〇) is added with an acrylate (丨·〇_2·〇 equivalent, preferably 1.5 equivalents) and a base such as DBU (0.3-1.0 equivalent, preferably 0.5 equivalent) in an acetonitrile solution. The mixture was stirred overnight at about 5 ° C. The solvent was removed under reduced pressure and the crude product was dissolved in EtOAc. EtOAc was washed with brine, dried with EtOAc EtOAc EtOAc. The product is further purified by chromatography or recrystallization. Example of General Procedure I: 3-(4-(3-(3-Ga-4-isopropoxyphenyl)β1,2,4-oxadiazolyl)_1H吲Preparation of 哚-1-yl) tert-butyl propionate

在为60 C下於含3-(3-氯-4-異丙氧基苯基）-5_(1H-吲哚_4· 基）可一吐（5.6克，15.83毫莫耳）之乙腈（55·9毫升）溶 液中滴加丙烯酸第二丁酯（3 45毫升，毫莫耳），接著 127788.doc -94- 200840567 滴加DBU(1.193毫升，7·91毫莫耳）。使混合物在約5〇°C下 攪拌隔夜。減壓移除溶劑且使粗製產物溶於DCM( 150毫 升）中，以鹽水（3x100毫升）洗滌且以MgS04脫水，經過濾 且減壓移除溶劑。自30-60°C之石油醚再結晶，獲得3-(4-(3-(3 -氣-4 -異丙氧基苯基）-1，2,4-号二吐-5-基）-1Η-σ引蜂-1 -基）丙酸第三丁酯（5.42克，69.6%)。LCMS(表1，方法b) Rt=3.03 min，m/z 482.26 (M+H)+ 〇 通用程序J :以溴化物使吲哚烷化 於含。引p朵（〇·9-1 ·2當置，較好1 · 〇當量）之適宜溶劑如dmf 溶液中添加NaH(0.9-1.2當量，較好ι·ι當量）。約15分鐘 後，添加烷基溴（0·9-2·0當量，較好ι·5當量）且使反應混合 物加熱至約50°C。約24小時後，使反應混合物冷卻至周圍 溫度，蒸發至乾且使粗製產物經層析進一步純化。 通用程序J之舉例： 4-(4-(3-(3 -氣-4-異丙氧基苯基）-1，2,4·吟二唾-5-基） 哚-1-基）丁酸第三丁酯之製備Acetonitrile with a spit (5.6 g, 15.83 mmol) in a solution containing 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indole-4) group at 60 C ( 5·9 ml) was added dropwise to the solution of dibutyl acrylate (3 45 ml, millimolar), followed by 127788.doc -94-200840567 DBU (1.193 ml, 7.91 mmol) was added dropwise. The mixture was allowed to stir overnight at about 5 °C. The solvent was removed under reduced pressure and the crude material was crystalljjjjjjjjjjjjjjjjjj Recrystallization from petroleum ether at 30-60 ° C to obtain 3-(4-(3-(3- gas-4-isopropoxyphenyl)-1,2,4-dioxa-5-yl) -1Η-σ cited bee-1 -yl) tert-butyl propionate (5.42 g, 69.6%). LCMS (Table 1, Method b) Rt = 3.03 min, m/z 482.26 (M+H) + 〇 General procedure J: Benzene was succinated by bromide. A suitable solvent such as p (9···2, preferably 1 · 〇 equivalent) is added, for example, NaH (0.9-1.2 equivalent, preferably ι·ι equivalent) is added to the dmf solution. After about 15 minutes, alkyl bromide (0·9-2·0 equivalents, preferably ι·5 equivalents) was added and the reaction mixture was heated to about 50 °C. After about 24 hours, the reaction mixture was cooled to ambient temperature, evaporated to dryness and then purified and purified An example of the general procedure J: 4-(4-(3-(3- gas-4-isopropoxyphenyl)-1,2,4·吟disindol-5-yl) 哚-1-yl) Preparation of acid tert-butyl ester

於含3-(3-氯-4-異丙氧基苯基）一5-(1Η-口引口朵-4-基）j 2 4的 二唑（0，100克，0·283毫莫耳）之DMF(0.999毫升）溶、夜中办 加NaH(0.012克，0.311毫莫耳）。約15分鐘後，添加4、、臭 酸第三丁酯（0.095克，0.424毫莫耳）且使反應混合物 至約50°C。約24小時後，使反應混合物冷卻至 β固溫度， 127788.doc -95- 200840567 經真空濃縮且在矽膠上層析（以Et0Ac/庚烷溶離）純化，獲 得無色油之4-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-嘮二唑-5- 基MH-吲哚-i_基）丁酸第三丁酯（〇 13S克，93%)，該油於 靜置後固化。LCMS(表 1，方法 c) Rt=3.50 min，m/2 496 (M+H)+ 〇 通用程序K:第三丁酯之去保護 於含第三丁酯（〇·9-1.2當量，較好1.0當量）之適宜溶劑如 DCM溶液中添加三氟乙酸（15_25當量，較好2〇當量）。使混 合物在周圍溫度下攪拌約8小時。減壓移除溶劑且使粗製 產物經層析或再結晶進一步純化。 通用程序Κ之舉例： 3-(4-(3-(3-氣-4-異丙氧基苯基）_ι，2,4·〃号二唑-5-基）-1H-吲 味-1-基）丙酸之製備a diazole containing 3-(3-chloro-4-isopropoxyphenyl)-5-(1Η- 口口口-4-yl)j 2 4 (0,100 g, 0·283 mmol) The ear of DMF (0.999 ml) was dissolved, and NaH (0.012 g, 0.311 mmol) was added in the night. After about 15 minutes, 4, tert-butyl odorate (0.095 g, 0.424 mmol) was added and the reaction mixture was brought to about 50 °C. After about 24 hours, the reaction mixture was cooled to a β solid temperature, 127788.doc -95 - 200840567 was concentrated in vacuo and purified on silica gel eluting with Et0Ac / heptane to afford 4-(4-( 3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl MH-indole-i-yl)butyric acid tert-butyl ester (〇13S, 93%), the oil solidified after standing. LCMS (Table 1, Method c) Rt = 3.50 min, m / 2 496 (M + H) + 〇 General procedure K: Deprotection of the third butyl ester A suitable solvent such as tributyl ester (〇·9-1.2 equivalent, preferably 1.0 equivalent) is added to a solution of DCM in a solution of trifluoroacetic acid (15-25 equivalents, preferably 2 equivalents). The mixture is stirred at ambient temperature for about 8 hours. The solvent is removed by pressure and the crude product is further purified by chromatography or recrystallization. Example of general procedure :: 3-(4-(3-(3-)-4-isopropoxyphenyl)_ι, 2,4 Preparation of oxadiazol-5-yl)-1H-anthracene-1-yl)propionic acid

TFATFA

於含3-(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-喝二唑-5-基）- 1H-吲哚-1-基）丙酸第三丁酯嘮二唑（5 25克，1〇·89毫莫耳） 之DCM(136毫升）溶液中添加三氟乙酸（16·78毫升，218毫 莫耳）。使混合物在周圍溫度下攪拌約8小時。減壓移除溶 劑且以乙醚使所得殘留物研散，獲得3-(4-(3_(3_氯_心異丙 氧基苯基）_1，2,4-吟二唑_5_基）·1Η•吲哚基）丙酸（4·35 克 ’ 93、〇%)° LCMS(表 1，方法b) Rt=3.03 min，w/z 356.13 (M-H) ; NMR (400 MHz，DMSO) δ 12·39 (s，iH)，8·13 127788.doc -96- 200840567 (叫 1H)，8·〇7 (m，1Η)，8·00 (d，IH)，7.94 (d，1H)，7.7 (d 1H), 7.41 (m, 2H), 7.18 (d, 1H), 4.84 (s, 1H), 4.53 (td 2H) 2.82(td，2H)，l.36(d 6H)。 ’ 通用程序L·芳基南之胺化 於微波反應瓶中添加芳基氟化物或漠化物（較好為氣化 物）(0,9-1.2當量，較好1〇當量）、胺（〇9_15當量，較好11 當量）、、石炭酸鉀（1.5-3·〇當量，車交好2·〇當量）及適宜溶劑如 DMF或DMA(較好為dmf)。將反應瓶蓋住且在配合冷卻下 _ 於14(K2〇〇°C(較好bOt)下加熱15-45分鐘（較好30分鐘）。 使粗製產物經層析進一步純化。 通用程序I之舉例·· (lR，3S)_3-(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-噚二唑·5_ 基） 苯基胺基）環戊燒甲酸之製備3-(4-(3-(3-Ga-4-isopropoxyphenyl)-1,2,4-dioxazol-5-yl)-1H-indol-1-yl) Trifluoroacetic acid (16.78 ml, 218 mmol) was added to a solution of the acid succinimide oxadiazole (5 25 g, 1 〇 89 mM). The mixture was allowed to stir at ambient temperature for about 8 hours. The solvent was removed under reduced pressure and the residue obtained was crystallised from diethyl ether to give 3-(4-(3-(3-chloro-p-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl) ·1Η•吲哚基)propionic acid (4·35 g '93, 〇%) ° LCMS (Table 1, Method b) Rt = 3.03 min, w/z 356.13 (MH); NMR (400 MHz, DMSO) δ 12·39 (s,iH),8·13 127788.doc -96- 200840567 (called 1H),8·〇7 (m,1Η),8·00 (d,IH),7.94 (d,1H), 7.7 (d 1H), 7.41 (m, 2H), 7.18 (d, 1H), 4.84 (s, 1H), 4.53 (td 2H) 2.82 (td, 2H), l.36 (d 6H). 'General procedure L. aryl South amination in the microwave reaction bottle to add aryl fluoride or desertification (preferably gasification) (0,9-1.2 equivalents, preferably 1 equivalent), amine (〇9_15 Equivalent, preferably 11 equivalents), potassium carbaate (1.5-3·〇 equivalent, good car exchange 2·〇 equivalent) and a suitable solvent such as DMF or DMA (preferably dmf). The reaction flask is capped and heated under combined cooling at 14 (K2 ° C (preferably bOt) for 15-45 minutes (preferably 30 minutes). The crude product is further purified by chromatography. General Procedure I Example··(lR,3S)_3-(4-(3-(3-Gas-4-isopropoxyphenyl)-1,2,4-oxadiazole·5-yl)phenylamino) ring Preparation of pentane formic acid

使3-(3-氣-4-異丙氧基苯基）-5-(4-氟苯基）-1，2,4-嘮二唑 (360毫克，1.082毫莫耳）、（ir，3S)_3_胺基環戊烷曱酸（154 毫克，1.190毫莫耳）、碳酸鉀（3 29毫克，2.380毫莫耳）及 DMF(2毫升）配合冷卻下在Biotage微波上及在160°C加熱3 0 分鐘。混合物以DMSO(6毫升）及MeCN(8毫升）稀釋，經過 濾且分成8等份，藉分子離子導入之LCMS純化。合併溶離 份且蒸發，獲得淺棕色固體，使之在真空中及約60°C下乾 燥約3小時。此獲得淺棕色固體之（lR，3S)-3-(4-(3-(3-氯-4- 127788.doc -97- 200840567 異丙氧基苯基）-1，2,4-呤二唑-5-基）苯基胺基）環戊烷甲酸 (212毫克，0.480毫莫耳，產率44.3%)。LCMS(表1，方法 a) Rt=3,49 min，m/z 440.20 (M-Η)·。1H NMR (400 MHz， DMSO- ppm 4·81 (s，1H)，3·96-3·76 (m，1H)，2,78 (s，1H)， 2.42-2.25 (m，1H)，2.12-1.95 (m，1H)，1.89 (d，J = 7.72 Hz， 2H)，1·73-1·61 (m，1H)，1.61-1.48 (m，1H)，1.39-1.30 (m， 7H)5 12.22-12.07 (m? 1H)? 6.73 (d9 1=8.82 Hz? 2H), 6.87- 6.79 (m，1H)，7.36 (d5 J=8.63 Hz，1H)，7·87 (d，J = 8.59 Hz， 2H)，7.98 (ddd，J=9.78，1.97，1.06 Hz，2H)。 通用程序M:烷基溴及酚之Mitsonubu反應 以冰/合使含二笨基膦（09-1.2當量，較好i.o當量）之適宜 溶劑如THF冷卻至0它。攪拌15分鐘後，滴加偶氮二甲酸 二異丙酯（0.9-1.2當量，較好1〇當量）歷時5分鐘。使反應 混合物在（TC下攪拌30分鐘。接著於混合物中添加含酚 (0.9-1.2當量，較好u當量）及烷基溴（〇9_12當量，較好 〇·9當量）之適宜溶劑如THF，使溫度維持在〇艺或以 下。使混合物在(TC下攪拌2小時，接著緩慢升溫至周圍溫 度且攪拌週。真空濃縮混合物，且使粗製產物經層析進 一步純化。 通用程序Μ之舉例： 4-(2-第三丁氧基側氧基乙氧基）苯甲酸苄酯之製備 127788.doc -98- 2008405673-(3-Actyl-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (360 mg, 1.082 mmol), (ir, 3S)_3_Aminocyclopentane decanoic acid (154 mg, 1.190 mmol), potassium carbonate (3 29 mg, 2.380 mmol) and DMF (2 mL) with cooling under Biotage microwave at 160° C is heated for 30 minutes. The mixture was diluted with DMSO (6 mL) and MeCN (8 mL), filtered and partitioned to aliquot. The combined fractions were combined and evaporated to give abrown brown solid, which was dried in vacuo and at about 60 ° C for about 3 hours. This gave (lR,3S)-3-(4-(3-(3-chloro-4-127788.doc-97-200840567 isopropoxyphenyl)-1,2,4-anthracene as a light brown solid. Zyrid-5-yl)phenylamino)cyclopentanecarboxylic acid (212 mg, 0.480 mmol, yield 44.3%). LCMS (Table 1, Method a) Rt = 3, 49 min, m/z 440.20 (M - Η). 1H NMR (400 MHz, DMSO-ppm 4·81 (s, 1H), 3·96-3·76 (m, 1H), 2,78 (s, 1H), 2.42-2.25 (m, 1H), 2.12 -1.95 (m,1H), 1.89 (d, J = 7.72 Hz, 2H), 1·73-1·61 (m,1H), 1.61-1.48 (m,1H), 1.39-1.30 (m, 7H) 5 12.22-12.07 (m? 1H)? 6.73 (d9 1=8.82 Hz? 2H), 6.87- 6.79 (m,1H), 7.36 (d5 J=8.63 Hz, 1H), 7·87 (d, J = 8.59) Hz, 2H), 7.98 (ddd, J=9.78, 1.97, 1.06 Hz, 2H). General procedure M: alkyl bromide and phenolic Mitsonubu reaction with ice/combination containing diphenylphosphine (09-1.2 equivalents, A suitable solvent such as THF is cooled to 0. After stirring for 15 minutes, diisopropyl azodicarboxylate (0.9-1.2 equivalents, preferably 1 equivalent) is added dropwise over 5 minutes. Stir for 30 minutes at TC. Then add a suitable solvent such as THF containing phenol (0.9-1.2 equivalents, preferably u equivalent) and alkyl bromide (〇9-12 equivalents, preferably 〇·9 equivalents) to the mixture to maintain the temperature. 〇艺或以下. The mixture was stirred at (TC for 2 hours, then slowly warmed to ambient temperature and stirred for a week. The mixture was concentrated in vacuo and allowed to The product further purified by chromatography system into the general procedure of Example Μ: Preparation of 4- (2-tert-butoxy-oxo-ethoxy) benzoate of 127788.doc -98- 200840567

於100毫升圓底瓶中於丙酮（100毫升）中混合4-羥基苯甲 酸苄酯（1.445克，6·33毫莫耳）及碳酸鉀（4.17克，30.1毫莫 耳）。滴加2-溴乙酸第三丁酯（0.908毫升，6.03毫莫耳）。使 溶液在65°C下攪拌隔夜。使溶液冷卻，接著使反應混合物 經燒結玻璃漏斗過濾。濃縮濾液獲得淺黃色油，使之經矽 膠層析（40克，30% EtOAc/庚烷）純化，獲得4-(2-第三丁氧 基-2-侧氧基乙氧基）苯甲酸节自旨（2.〇6克，5.90毫莫耳，產 率 98%)之無色油。LC/MS(方法 A) 1=4.31 min。 通用程序N:脫苄基化作用 於高壓瓶中加入在鈀/碳（〇·9-1.2當量，較好1.〇當量）， 接著饋入適宜溶劑如MeOH(200毫升），接著添加苯曱酸酯 (50-70當量，較好60當量）。使所得懸浮液在氫氣（35 ps〇 中及周圍溫度下搖晃2小時。使混合物經Celite®過濾且濃 縮無色濾液，獲得產物。 通用程序N之舉例： 4_(2 -第二丁氧基-2-側氧基乙氧基）苯甲酸之製備Benzyl 4-hydroxybenzoate (1.445 g, 6.33 mmol) and potassium carbonate (4.17 g, 30.1 mmol) were mixed in acetone (100 mL) in a 100 mL round bottom flask. T-butyl 2-bromoacetate (0.908 ml, 6.03 mmol) was added dropwise. The solution was allowed to stir overnight at 65 °C. The solution was allowed to cool and the reaction mixture was filtered through a fritted glass funnel. The filtrate was concentrated to give a pale yellow oil which was purified eluting eluting eluting eluting eluting A colorless oil from the purpose of (2. 6 g, 5.90 mmol, 98% yield). LC/MS (Method A) 1 = 4.31 min. General Procedure N: Debenzylation is carried out in a high pressure bottle by addition of palladium on carbon (〇·9-1.2 equivalents, preferably 1. 〇 equivalent), followed by feeding into a suitable solvent such as MeOH (200 mL) followed by the addition of phenylhydrazine. Acid ester (50-70 equivalents, preferably 60 equivalents). The resulting suspension was shaken in hydrogen (35 psi) at ambient temperature for 2 hours. The mixture was filtered through Celite® and concentrated to give a coloured filtrate to give the product. Example of General Procedure N: 4_(2 - 2 -butoxy-2 Preparation of -oxy ethoxy)benzoic acid

於500毫升高壓瓶中饋入含4_(2_第三丁氧基_2_側氧基乙 127788.doc •99· 200840567 氧基）苯甲酸节醋（2.〇6克’ 6.〇2毫莫耳）之甲醇（⑽毫升）。 添加在叙/碳（G.320克，〇.3()1毫莫耳），使所得懸浮液在氮 氣（47psi)中及室溫下搖晃6小_。使混合物經⑸心⑧過 濾，濃縮無色濾液，獲得淺黃色固體之4_(2_第三丁氧基_ 2-側氧基乙氧基）苯甲酸（1.5克，5 95毫莫耳，產率 LC/MS(^-^A) Ri=3.03 min.; MS m/z: 251.30 (M-H)'〇 1H NMR (400 MHz，溶劑 d_DMS〇) ppm 7 88 ⑷ 99 Hz，Into a 500 ml high pressure bottle, feed 4_(2_3 butyloxy_2_sideoxyethyl 127788.doc •99·200840567 oxy)benzoic acid vinegar (2.〇6g' 6.〇2 Millol) of methanol ((10) ml). Add the carbon/carbon (G.320 g, 〇.3() 1 mmol) and shake the resulting suspension in nitrogen (47 psi) at room temperature for 6 hours. The mixture was filtered through (5) EtOAc (EtOAc) (EtOAc (EtOAc:EtOAc) LC/MS(^-^A) Ri=3.03 min.; MS m/z: 251.30 (MH) '〇1H NMR (400 MHz, solvent d_DMS〇) ppm 7 88 (4) 99 Hz,

2H), 6.98 (d, /=9.00 Hz, 2H), 4.75 (s, 2H), 1.43 (s, 9H) 〇 通用程序〇··經保護12-二醇之去保護作用 於含經保護二醇（0.9-1.2當量，較好！ 〇當量）之適宜溶劑 如溶液中添加1 M HC1溶液（1.5-2.5當量，較好2·〇當 量）。使混合物加熱至7(TC歷時約2小時。冷卻至周圍溫: 後’添加驗水溶液如！ Μ Ν_且真空濃縮反應混合物二 所得固體以大量水洗蘇且真空乾燥，獲得產物。 通用程序〇之舉例： ((3 (3氣異丙氧基苯基）114噚二唑·5_基）苯氧基） 丙烧-I，2·二醇之製備2H), 6.98 (d, /=9.00 Hz, 2H), 4.75 (s, 2H), 1.43 (s, 9H) 〇General procedure〇··protection of protected 12-diol to protected diol A suitable solvent (0.9-1.2 equivalent, preferably 〇 equivalent) is added to the solution as a solution of 1 M HCl solution (1.5-2.5 equivalents, preferably 2 〇 equivalent). The mixture is heated to 7 (TC for about 2 hours. Cooling to ambient temperature: after 'addition of an aqueous solution such as! Μ Ν _ and concentrating the reaction mixture in vacuo to obtain a solid which is washed with a large amount of water and dried under vacuum to obtain a product. Example: Preparation of ((3 (3-isopropoxyphenyl) 114 oxadiazole·5-yl)phenoxy)propane-I,2·diol

、 乳異丙氧基苯基）-5-(4-((2,2-二甲基_ι，3·二^ 雜環戊1基）甲氧基）苯基）]，2,4令哇（(Μ克， 耳）及對Τ苯石讀單水合物（8 55毫克，〇〇45毫莫耳）: 於甲醇（2’升）中。使反應混合物在7G°C下加熱16小時。 I27788.doc -100- 200840567 使浴液冷卻，將曱醇（1 ·5毫升）添加於混合物中且再結晶， 所得懸浮液經過濾，以大量水洗滌固體，獲得白色固體之 3-(4-(3-(3-氯-4-異丙氧基苯基号二唑基）笨氧基） 丙烷 _1，2_二醇（〇,〇8 克，0.198 毫莫耳，產率 88%)。lc/ms, isopropylisopropoxyphenyl)-5-(4-((2,2-dimethyl-methyl), bis-cyclopentyl) methoxy)phenyl)], 2, 4 Wow ((Μ克, ear) and parabens read monohydrate (8 55 mg, 〇〇45 mmol): in methanol (2' liter). Heat the reaction mixture at 7G °C for 16 hours. I27788.doc -100- 200840567 The bath was cooled, decyl alcohol (1.5 ml) was added to the mixture and recrystallized, and the resulting suspension was filtered, and the solid was washed with a large amount of water to obtain a white solid 3-(4) -(3-(3-chloro-4-isopropoxyphenyl)diazolyloxy)propane-1,2-diol (〇, 〇8 g, 0.198 mmol, yield 88%) ).lc/ms

(純度 QC) R，=2.97 min·; MS m/z: 405.18 (M+H)+。1H NMR(Purity QC) R, = 2.97 min·; MS m/z: 405.18 (M+H)+. 1H NMR

(400 MHz，溶劑 d-DMSO) ppm 8· 1 6-8.09 (m，2H)，8 〇5 (d J二2·13 Hz，1H)，7.99 (dd，*/=8.64，2·15 Hz，1H)，7,38 (d J二9.05 Hz，1H)，7.25-7.16 (m，2H)，5·03 (d，J=5,19 Hz 1H)，4.87-4.78 (m，1H)，4·72 (t，《7=5.68 Hz，1H)，4·15 (dd J=3.97，10.01 Hz，1H)，4.01 (dd，J=6.20，10.03 Hz，1H) 3.84 (dt，/=4·04，5.69，5.91 Hz，1H)，3·47 (t，/=5.84 Hz 2H)，L35 (d，&gt;6.03 Hz，6H)。 利用通用程序之表 表Α·使用通用程序C、D、E進行之實例（反應圖2) 下列腈前驅物之括號中之字母代表製備腈前驅物之通用 程序(400 MHz, solvent d-DMSO) ppm 8· 1 6-8.09 (m, 2H), 8 〇 5 (d J 2·13 Hz, 1H), 7.99 (dd, */= 8.64, 2·15 Hz ,1H),7,38 (d J=9.05 Hz,1H), 7.25-7.16 (m,2H),5·03 (d,J=5,19 Hz 1H), 4.87-4.78 (m,1H), 4·72 (t, "7=5.68 Hz, 1H), 4·15 (dd J=3.97, 10.01 Hz, 1H), 4.01 (dd, J=6.20, 10.03 Hz, 1H) 3.84 (dt, /=4 04, 5.69, 5.91 Hz, 1H), 3·47 (t, /= 5.84 Hz 2H), L35 (d, &gt; 6.03 Hz, 6H). Table using general procedures Table Α Example using general procedures C, D, E (Reaction Figure 2) The letters in parentheses of the following nitrile precursors represent the general procedure for preparing nitrile precursors.

nh2 ,ΟΗ酸或酿氯 r-Ci N — x 通用程序 χ 通用程序Nh2 , tannic acid or brewed chlorine r-Ci N — x general procedure χ general procedure

r D或E 127788.doc -101 - 200840567 實例 編號 A.1 A.2 A.3 A.4 A.5 A.6 Α·7 Α.8 腈前羅物 酸或醯氣 產物 3-氯-4·環丙基 曱氧基-苄腈 (B) 2-甲基·苯甲 醯氯r D or E 127788.doc -101 - 200840567 Example No. A.1 A.2 A.3 A.4 A.5 A.6 Α·7 Α.8 Nitrile rosin or helium product 3-chloro- 4·Cyclopropyl decyloxy-benzonitrile (B) 2-methyl·benzhydryl chloride

名稱 3-(3-氯-4-環丙 基曱氧基-苯 基)-5-鄰-曱苯 基-[1，2,4] 口咢二 口坐Name 3-(3-Chloro-4-cyclopropyl decyloxy-phenyl)-5-o-indolyl-[1,2,4]

Rt/min (方法） 2.94 (b) nt/z 4-丁氧基-3- 氯-节腈 (B) 曱基-笨甲 醯氯Rt/min (method) 2.94 (b) nt/z 4-butoxy-3-chloro-nodal nitrile (B) mercapto-accumin

3-(4-丁氧基-3-氯-笨基)-5务 曱苯基-[1，2,4] 口咢二嗤 3.10 ⑼ 342 (M-H)- 3-氯-4-異丁氧 基-节腈 (B) 2-甲基-笨甲 酿氯3-(4-Butoxy-3-chloro-phenyl)-5-indole phenyl-[1,2,4] oxime oxime 3.10 (9) 342 (MH)- 3-chloro-4-isobutoxy Base-nodal nitrile (B) 2-methyl-brown

3-[3-氯-4-(1-曱 基-環丙基曱氧 基;l·苯基]-5-鄰-甲苯基-[1，2,4] p号二口坐 3.11 (b) 342 (M-H)' 3-氯-4-(1-甲 基-環丙基甲 氧基)-节腈(B) 2-甲基-笨甲 醯氯3-[3-Chloro-4-(1-indolyl-cyclopropylhydroxyl; l-phenyl]-5-o-tolyl-[1,2,4] p No.2 3.11 (b ) 342 (MH)' 3-Chloro-4-(1-methyl-cyclopropylmethoxy)-mercaptonitrile (B) 2-methyl-parasinyl chloride

3-[3-氯-4-(1-甲 基-環丙基曱氧 基)-苯基]-5-鄰- 曱苯基4U，4] 口咢二口坐 3.08(b) 3-氯-4-戊氧 基-节腈 (B) 2_甲基-苯曱 醯氣3-[3-Chloro-4-(1-methyl-cyclopropyl decyloxy)-phenyl]-5-o-indolephenyl 4U,4] 2-nose 3-nose 3.08(b) 3-chloro -4-pentyloxy-ruthenium nitrile (B) 2-methyl-benzoquinone

3-(3-氯-4-戍氧 基-苯基)-5-鄰-曱苯基-[1，2,4] 口咢二唾 3.20(b) 356 (M-H)' 3-氯-4-(3,3-二 甲基-丁氧基)-苄腈 (Β) 2-甲基、笨甲 醯氣3-(3-Chloro-4-indolyl-phenyl)-5-o-indolephenyl-[1,2,4] oxime disaponin 3.20(b) 356 (MH)' 3-chloro-4 -(3,3-dimethyl-butoxy)-benzonitrile (Β) 2-methyl, stupid

3-[3_氣-4-(3,3· 基)-苯基]-5-鄰- 甲本基-[1，2,4] 口号二口坐 3.27 (b) 370 (M-H)’ 3-氯-4-環戊基 曱氧基-苄腈 (Β) 2_甲基-笨甲 酿氯3-[3_Gas-4-(3,3·yl)-phenyl]-5-o-methyl-based-[1,2,4] Slogan two-seat 3.27 (b) 370 (MH)' 3 -chloro-4-cyclopentyl decyloxy-benzonitrile (Β) 2_methyl-brown

3-(3-氯-4-環戊 基甲氧基-苯 基)-5-鄰-曱苯 基-[1，2,4]噚二 口坐 3.26 (b) 368 (M-H)' 3-氯-4-(2-乙 基-丁氧基)-苄 腈⑻ 2_甲基-笨甲 醯氣3-(3-Chloro-4-cyclopentylmethoxy-phenyl)-5-o-indolephenyl-[1,2,4]噚 two-seat 3.26 (b) 368 (MH)' 3- Chloro-4-(2-ethyl-butoxy)-benzonitrile (8) 2-methyl-bymazan

H3-氯冬(2-乙 基-丁氧基)-苯 基]_5·鄰-甲苯 基-[1，2#]噚二 口坐 3.34 (b) 370 (M-H)' 127788.doc -102 200840567H3-Chloro(2-ethyl-butoxy)-phenyl]_5·o-tolyl-[1,2#]噚2 sitting 3.34 (b) 370 (M-H)' 127788.doc -102 200840567

實例 編號 A.9 A.10 A.11 A.12 A.13 A.14 A.15 A.16 腈前驅物 酸或醯氣 產物 名稱Example No. A.9 A.10 A.11 A.12 A.13 A.14 A.15 A.16 Nitrile precursor Acid or helium Product Name

Rt/min(方法） m/z 3-氯-4-辛氧 基-节腈 (B) 2-甲基-苯甲 醯氯Rt/min (method) m/z 3-chloro-4-octyloxy-pyridinonitrile (B) 2-methyl-benzoic acid

3-氣-4-(3-甲氧 基-丙氧基)-苄 腈 (B) 3-氯-4-(3-乙氧 基-丙氧基)-苄 腈 (B) 2-甲基-笨甲 醯氯 3·氯-4-(2-口底 0定-1-基·乙氧 基)-节腈 (B) 3-氯-4-(2-嗎 琳-4-基-乙氧 基)-苄腈 (B)3-ox-4-(3-methoxy-propoxy)-benzonitrile (B) 3-chloro-4-(3-ethoxy-propoxy)-benzonitrile (B) 2-methyl -Puppy, chloroform, chloro-4-(2-indolyl), hexanyl ethoxyl (B) 3-chloro-4-(2-morphin-4-yl-B Oxy)-benzonitrile (B)

2·甲基-笨甲 醯氯 3-氯-4-環戊氧 基-节腈 (B) 曱基**笨曱 醯氯2·Methyl-Bute A 醯Chlorine 3-Chloro-4-cyclopentyloxy-ruthenium nitrite (B) 曱 ** 曱 曱 曱 醯 醯

3-氯-4-(1-乙 基-丙氧基)-苄 腈(B) 2-甲基&quot;笨甲 醯氯3-chloro-4-(1-ethyl-propoxy)-benzonitrile (B) 2-methyl &quot;

3-(3-氯-4-辛氧 基-苯基)-5-鄰-甲苯基-[1，2,4] 口号二口坐 3-[3-氯_4-(3-甲 氧基-丙氧基)-苯基]-5-鄰-甲苯 基-[1，2,4]嘮二 σ坐 3-[3-氯-4-(3-乙 氧基-丙氧基)-苯基]孓鄰-曱苯 基-[1，2,4]咩二 口坐 -{2-[2^-4-(5-鄰·甲苯基-[1，2,4]嘮二唑-3-基)-苯氧基]-乙 基}-旅啶 4- {2-[2-氣-4-(5-鄰-曱苯基-1，2,4]噚二唑-3. 基)-苯氧基]-乙 基}-嗎琳 3-(3-氯-4-環戊 氧基-苯基)-5-鄰-曱苯基-[1，2,4]呤二唑 3-P-氯-4-(1-乙 基-丙氧基)-苯 基]-5-鄰-曱苯 基-[1，2,4]嘮二 口坐 3.60(b) 2.86 (b) 2.95(b) 2.32 (b) 2.59(b) 3.14(b) 3.18(b) 397 (M-H)· 399 (M-H)· 354 (M-H)- 356 (M-H)' 3-氯-4-環己氧 基-苄腈 (B) 孓曱基··笨甲 醯氯3-(3-chloro-4-octyloxy-phenyl)-5-o-tolyl-[1,2,4] sip two-spot 3-[3-chloro-4-(3-methoxy) -propoxy)-phenyl]-5-o-tolyl-[1,2,4]indole yttrium 3-[3-chloro-4-(3-ethoxy-propoxy)-benzene孓] 孓-曱-phenyl-[1,2,4]咩 two-seat-{2-[2^-4-(5-o-tolyl-[1,2,4]oxadiazole-3 -yl)-phenoxy]-ethyl}-brupidine 4-{2-[2- gas-4-(5-o-indolylphenyl-1,2,4]oxadiazole-3.yl) -phenoxy]-ethyl}-morphine 3-(3-chloro-4-cyclopentyloxy-phenyl)-5-o-indolephenyl-[1,2,4]oxadiazole 3- P-chloro-4-(1-ethyl-propoxy)-phenyl]-5-o-indolephenyl-[1,2,4]唠 two sits 3.60 (b) 2.86 (b) 2.95 ( b) 2.32 (b) 2.59(b) 3.14(b) 3.18(b) 397 (MH)· 399 (MH)· 354 (MH)- 356 (MH)' 3-Chloro-4-cyclohexyloxy-benzyl Nitrile (B) sulfhydryl

3-(3-氯-44裒己 氧基-苯基)-5-鄰-曱苯基-[1，2,4]嘮二唑 3.22 (b) 368 (M-H)· 127788.doc •103- 2008405673-(3-Chloro-44-hexyloxy-phenyl)-5-o-indolephenyl-[1,2,4]oxadiazole 3.22 (b) 368 (MH)· 127788.doc •103- 200840567

實例 編號 A.17 A.18 A.19 A.20 A.21 A.22 A.23 A.24 腈前驅物 3-氯-4-苯乙氧 基-节腈(B) 3-氯-4-(3-甲 基-丁氧基)-节 腈(B) 酸或醯氣 產物 名稱Example No. A.17 A.18 A.19 A.20 A.21 A.22 A.23 A.24 Nitrile precursor 3-chloro-4-phenylethoxy-quinone (B) 3-chloro-4 -(3-Methyl-butoxy)-nickel (B) acid or helium product name

Rt/min (方法) m/z 2-甲基-苯甲 醯氯Rt/min (method) m/z 2-methyl-benzoic acid

3-(3-氯-4-苯乙 氧基-苯基)-5-鄰•曱苯基-[1，2,4]噚二唑 3.04(b) 孓甲基·苯甲 醯氯3-(3-Chloro-4-phenylethoxy-phenyl)-5-o-indolephenyl-[1,2,4]oxadiazole 3.04(b) 孓methyl·benzamide 醯chloro

3-[3-氣-4-(3-曱 基-丁氧基)-苯 基]-5-鄰-甲苯 基-[1，2,4]噚二 口坐 3.19(b) 曱基**笨甲 醯氯 3-氣-4-環己基 曱氧基-苄腈 (B) 3-氯-4-(2-異丙 氧基-乙氧基)-苄腈 (B)3-[3-Ga-4-(3-indolyl-butoxy)-phenyl]-5-o-tolyl-[1,2,4]噚 two-seat 3.19(b) fluorenyl ** Chlorpyrifos 3-chloro-4-cyclohexyloxy-benzonitrile (B) 3-chloro-4-(2-isopropoxy-ethoxy)-benzonitrile (B)

3-(3-氯-4-環己 基曱氧基•苯 基)-5-鄰-曱苯 基-[1，2,4] 口咢二 口坐 2-甲基-笨甲 隨氯 3-P-氯-4-(2-異 丙氧基-乙氧 基)-苯基]-5-鄰-甲苯基-[1，2,4]噚二唑 3.39(b) 2.91 (b) 382 (M-H)- 372 (M-H)' 3-氣-4-戊-3-炔 基氧基-节腈 (B) 厶甲基-笨甲 醯氯3-(3-Chloro-4-cyclohexyloxyoxyphenyl)-5-o-indolephenyl-[1,2,4] 2-position 2-methyl-accumin with chlorine 3- P-chloro-4-(2-isopropoxy-ethoxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole 3.39(b) 2.91 (b) 382 ( MH)- 372 (MH)' 3-Actyl-4-pent-3-ynyloxy-pyridinonitrile (B) 厶Methyl-Arachnid

3 **(3 -氯-4-戍-3 · 3-氣-4-(2-嗟 吩-2-基-乙氧 基)-苄腈 (B) 4-第二丁氧基 3-氯·苄腈 (B) 3-氯-4-(2-二甲 胺基-1-甲基-乙氧基)-苄腈(B) 127788.doc 基)-5-鄰-曱苯 基-[1，2,4]呤二 σ坐 2.90(b) 352 (M-H)· 2-甲基-笨甲 酿氯3 **(3-Chloro-4-indole-3-yt-4-(2-indol-2-yl-ethoxy)-benzonitrile (B) 4-second butoxy 3-chloro ·Benzonitrile (B) 3-chloro-4-(2-dimethylamino-1-methyl-ethoxy)-benzonitrile (B) 127788.doc)-5-o-indolephenyl-[ 1,2,4]呤二σ sit 2.90(b) 352 (MH)· 2-methyl-brown

3-P-氣-4-(2-噻 吩-2-基·乙氧 基)-苯基]-5-鄰-甲苯基-[1,2,4]嘮二唑 2-曱基-笨甲 醯氯3-P-gas-4-(2-thien-2-ylethoxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole 2-mercapto-acne Chlorine

3-(4-第二丁氧 基-3-氣-苯基)-5-鄰-曱苯基一 [1，2,4]嘮二唑 3.00 (b) 3.07 (b) 396 (M-H)· 342 (M-H)· 2-曱基-苯甲 酿氯3-(4-Secondoxy-3-oxo-phenyl)-5-o-indolephenyl-[1,2,4]oxadiazole 3.00 (b) 3.07 (b) 396 (MH)· 342 (MH)· 2-Mercapto-Benzyl Chloride

{2-[2-氯-4-(5· 鄰-曱苯基-[1，2,4]噚二唑-3 基)·苯氧基]-丙 基l·二曱基胺 2.21 (b) 371 (M-H)' -104- 200840567 實例 編號 腈前騍物 酸或醢氣 產物 名稱{2-[2-Chloro-4-(5-o-indolyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-propyl-l-decylamine 2.21 (b ) 371 (MH)' -104- 200840567 Example number nitrile pro-antimony or helium product name

Rt/min (方法） m/z A.25 3-氣-4-(2-二甲 胺基-乙氧基)-2-苄腈 (B) 甲基-苯甲 酿乳Rt/min (method) m/z A.25 3-oxo-4-(2-dimethylamino-ethoxy)-2-benzonitrile (B) methyl-benzaldehyde

{2-[2-氯-4-(5-鄰·曱苯基-[1，2,4忾二唑各 基)·苯氧基]-乙 基}-二甲基胺 2.18(b) A.26 3-氯-4-環丁基 甲氧基·苄腈 (B) 2-甲基-苯曱 醯氣{2-[2-Chloro-4-(5-o-indolephenyl-[1,2,4oxadiazoleyl)-phenoxy]-ethyl}-dimethylamine 2.18(b) A .26 3-chloro-4-cyclobutylmethoxybenzonitrile (B) 2-methyl-benzoquinone

A.27 A.28 4-[(〇E)-丁-2. 烯基)氧基]-3_ 氯腈 (B) 3-氣-4-(4,4,4-三«I-丁氧基)-苄腈 (B) 2-曱基-苯曱 醯氯 2-甲基-苯甲 醯氯A.27 A.28 4-[(〇E)-butyl-2. alkenyl)oxy]-3_ chloronitrile (B) 3-ox-4-(4,4,4-tri«I-butoxy Base)-benzonitrile (B) 2-mercapto-benzoquinone chloride 2-methyl-benzhydryl chloride

H3-氯冰環丁 基曱氧基-苯 基)-5-鄰-曱苯 基-[152，外号二 口坐 3·{4-ϋ 稀基)氧基]-3-氯-苯基}-5-鄰· 曱苯基-[1，2,4]呤二唑 3.15(b) 354 (M-H)·H3-Chlorobutylidene decyloxy-phenyl)-5-o-indole phenyl-[152, nickname two-position 3·{4-ϋ 稀)oxy]-3-chloro-phenyl }-5-o-p-phenyl-[1,2,4]oxadiazole 3.15(b) 354 (MH)·

3-[3-氯冰(4,4,4- 三氟-丁氧基)-苯基]-5-鄰-甲苯 基-[1，2,4] 口咢二 U坐 2.96 (b) 340 (M-H)- 2.97 (b) 396 (M-H)' A.29 3-氣-4-(4-曱 基-環己基曱 氧基)-苄腈(B) 2-曱基-苯甲 酿^氣 XT'3-[3-Chloro(4,4,4-trifluoro-butoxy)-phenyl]-5-o-tolyl-[1,2,4] 咢2 U sitting 2.96 (b) 340 (MH)- 2.97 (b) 396 (MH)' A.29 3-Gas-4-(4-indolyl-cyclohexyldecyloxy)-benzonitrile (B) 2-indolyl-benzoic acid XT'

3-[3-氯·4-(4-曱 基-環己基曱氧 基)-苯基]-5-鄰-甲苯基-[1，2,4]吟二唑 3.50(b) 396 (M-H)- A.30 3-氯-4·異丙氧 基-节腈 (A) 吡嗪-2·甲酸3-[3-Chloro-4-(4-mercapto-cyclohexyloxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole 3.50(b) 396 (MH )- A.30 3-Chloro-4·isopropoxy-cyanocarbonitrile (A) Pyrazine-2·formic acid

2-[3-(3-氣-4-異 丙氧基-苯基)-[1，2,4妒咢二唑-5- 基；k比嗪 3.48 (a) 317(M+H)+ A.31 3-氣-4-異丙氧 基-节腈 (A) 異呤唑-3-甲 酸2-[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4oxadiazol-5-yl; k-pyrazine 3.48 (a) 317 (M+H)+ A.31 3-Gas-4-Isopropoxy- nitrite (A) Isoxazole-3-carboxylic acid

3-(3-氯-4-異丙 氧基-苯基)-5-異 呤唑-3-基-[1，2,4]呤二唑 3.57(a) 306 (M+H)+ A.32 3-氯-4-異丙氧 基*节腈 (A) 3-甲氧基-丙 酸3-(3-Chloro-4-isopropoxy-phenyl)-5-isoxazol-3-yl-[1,2,4]oxadiazole 3.57(a) 306 (M+H)+ A .32 3-Chloro-4-isopropoxy* hexanenitrile (A) 3-methoxy-propionic acid

3-(3-氣-4-異丙 氧基-苯基)-5-(2-曱氧基-乙 基)-Π，2,4] 口咢二 口坐 3.43 (a) 297 (M+H)+ 127788.doc -105- 2008405673-(3-Actyl-4-isopropoxy-phenyl)-5-(2-decyloxy-ethyl)-indole, 2,4] 2-nose sitting 3.43 (a) 297 (M+ H)+ 127788.doc -105- 200840567

實例 編號 A.33 A.34 A.35 A.36 Α.37 Α.38 Α.39 A.40 腈前驅物 3-氯-4-異丙氧 基-节腈 (A) 3-氯-4-異丙氧 基-节腈 ㈧ 3-氣-4-異丙氧 基-节腈 (A) 3-氯-4-異丙氧 基-节腈 (A) 3-氯-4-異丙氧 基-节腈 (Α) 3-氯-4-異丙氧 基-节腈 (Α) 3-氣-4-異丙氧 基-节腈 (Α) 3-氯-4-異丙氧 基-节腈(A) 127788.doc 酸或醯氣 異於驗酸 環丙基乙酸 於鹼酸 σ比咬-2-甲酸 2-甲基-笨甲 酸 3-曱基-異菸 鹼酸 3-氣-4-異丙 氧基-苯曱 酸 註a 產物 一 〇Example No. A.33 A.34 A.35 A.36 Α.37 Α.38 Α.39 A.40 Nitrile precursor 3-chloro-4-isopropoxy- nitrite (A) 3-chloro-4 -isopropoxy-n-nitrile (octa) 3-oxo-4-isopropoxy- nitrite (A) 3-chloro-4-isopropoxy- nitrite (A) 3-chloro-4-isopropoxy Base-nodal nitrile (Α) 3-chloro-4-isopropoxy- nitrite (Α) 3- gas-4-isopropoxy- nitrite (Α) 3-chloro-4-isopropoxy- Nitrile (A) 127788.doc Acid or helium is different from acid-treated cyclopropylacetic acid in alkali acid σ than bite 2-carboxylic acid 2-methyl-benzoic acid 3-mercapto-isonicotinic acid 3-gas- 4-isopropoxy-benzoic acid injection a product

名稱 4-[3·(3-氯-4-異 丙氧基-苯基)-[1，2,4]吟二唑-5. 基]-吡啶 3-(3-氯-4-異丙 氧基-苯基)-5-環 丙基曱基-[1，2,4]噚二唑 3-[3-(3-氣-4-異 丙氧基-苯基)· :l，2,4]^ί号二口坐-5-基]-σ比啶 2-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]-°比咬 3-(3-氯-4-isoprop氧基-苯 基)-5-鄰-甲苯 基-[1，2,4] 口咢二 口坐 4·[3-(3-氣-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]各曱基-吼咬 3,5-雙-(3-氣-4-異丙氧基-苯 基HU，4?咢二 唑 [3-(3-氣-4-異丙 氧基-苯基)-[1，2,4]噚二唑-5-基]_二甲基-胺Name 4-[3·(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5.yl]-pyridine 3-(3-chloro-4-isopropyl Oxy-phenyl)-5-cyclopropylindenyl-[1,2,4]oxadiazole 3-[3-(3- gas-4-isopropoxy-phenyl)· :l,2 , 4]^ί No. 2 -5-yl]-σ-pyridyl 2-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazole- 5-based]-° ratio biting 3-(3-chloro-4-isopropoxy-phenyl)-5-o-tolyl-[1,2,4] sputum two sitting 4·[3-( 3-oxo-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]indolyl-bite 3,5-bis-(3-gas-4-iso Propoxy-phenyl HU, 4? oxadiazole [3-(3- gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-dimethyl Base-amine

Rt/min(方法） 3.76(a) m/z 316(M+H)+ 3.88 (a) 293 (M+H)+ 2.37 (f) 316(M+H)+ 2.10(f) 316(Μ+Η)+ 2.62 (f) 329 (M+H)+ 2.70 (f) 330 (M+H)+ 2.81 (f) 407 (M+H)+ 2.03 (f) 282 (M+H)+ -106 - 200840567 實例 編號 腈前驅物 酸或醯氟 產物 名稱 Rt/min (方法） m/z A.41 3·氣4-異丙氧 基-节腈 (A) 苯基·•乙酸 5-苄基-3-(3-氯-4-異丙氧基-苯 基)-[1，2,4] 口咢二 σ坐 2.37 (f) 329 (M+H)+ A.42 3-氣-4-異丙氧 基-¥腈 (A) 笨曱酸 3-(3·氯-4·異丙 氧基-苯基)-5-苯 基-[1，2,4?咢二 口坐 2.50 (f) 315 (M+H)+ A.43 3-氣-4-異丙氧 基-节腈 (A) 吡啶-3-基-乙酸 N—0\ 3-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]巧二唑-5-基曱基]-π比咬 2.03 (f) 330 (M+H)+ A.44 3-氣-4-異丙氧 基-节腈 (A) 3-0比咬-3- 基-丙酸 N—〇\ 人 4-{2-[3-(3-氯-4-異丙氧基-苯 基)-[1，2,4]呤二 唑-5-基]-乙基}-°比咬 2.15(f) 344 (M+H)+ A.45 3-氯-4-異丙氧 基-节腈 (A) 3-三氟曱基-苯曱酸 3-(3-氯-4-異丙 氧基-苯基)-5-(3-三氟曱基-苯 基 Hl，2,4]噚二 口坐 4.33 (g) 382 (M)+ A.46 3-氯-4-異丙氧 基·节腈 ㈧ 4-甲基-戊酸 N-^°v 3-(3-氯-4·異丙 氧基-苯基)-5-(3-曱基-丁基)-[1，2,4]嘮二唑 2.90(b) 309 (M+H)+ A.47 3-氣-4·異丙氧 基-节腈 ㈧ 3,3-二曱基-丁酸 人 3-(3-氯-4-異丙 氧基-苯基)-5-(2,2-二曱基-丙 基)-[1，2,4]嘮二 口坐 2.88 (b) 309 (M+H)+ A.48 氯-4-異丙氧 基-节腈 (A) 庚酸 N—0、 3-(3-氯-4-異丙 氧基-苯基&gt;5-己 基-[1，2,4]喝二 σ坐 3.01 (b) 323.20 (M+H)+Rt/min (method) 3.76(a) m/z 316(M+H)+ 3.88 (a) 293 (M+H)+ 2.37 (f) 316(M+H)+ 2.10(f) 316(Μ+ Η)+ 2.62 (f) 329 (M+H)+ 2.70 (f) 330 (M+H)+ 2.81 (f) 407 (M+H)+ 2.03 (f) 282 (M+H)+ -106 - 200840567 Example number nitrile precursor acid or fluorene product name Rt/min (method) m/z A.41 3·gas 4-isopropoxy- nitrite (A) phenyl·•acetic acid 5-benzyl-3 -(3-chloro-4-isopropoxy-phenyl)-[1,2,4] 咢 咢 σ 2.3 2.37 (f) 329 (M+H)+ A.42 3- -4- Propoxy-acetonitrile (A) 3-(3·chloro-4·isopropoxy-phenyl)-5-phenyl-[1,2,4?咢2 sitting 2.50 (f) 315 (M+H)+ A.43 3-oxo-4-isopropoxy-cyanohydrin (A) pyridin-3-yl-acetic acid N—0\ 3-[3-(3-chloro-4-iso Propoxy-phenyl)-[1,2,4]codazole-5-ylindenyl]-π ratio bite 2.03 (f) 330 (M+H)+ A.44 3- gas-4-iso Propoxy-quiniononitrile (A) 3-0 than -3--3-propionic acid N-〇\ human 4-{2-[3-(3-chloro-4-isopropoxy-phenyl)- [1,2,4]oxadiazol-5-yl]-ethyl}-° ratio 2.15(f) 344 (M+H)+ A.45 3-chloro-4-isopropoxy- nitrite (A) 3-Trifluoromethyl-benzoic acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(3- Fluorinyl-phenyl Hl, 2, 4] bismuth sitting 4.33 (g) 382 (M) + A.46 3-chloro-4-isopropoxy methoxyl (8) 4-methyl-pentanoic acid N -^°v 3-(3-Chloro-4·isopropoxy-phenyl)-5-(3-indolyl-butyl)-[1,2,4]oxadiazole 2.90(b) 309 ( M+H)+ A.47 3-Gas-4·Isopropoxy-nickel (8) 3,3-Dimercapto-butyric acid 3-(3-chloro-4-isopropoxy-phenyl) -5-(2,2-Dimercapto-propyl)-[1,2,4]唠2 sitting 2.88 (b) 309 (M+H)+ A.48 chloro-4-isopropoxy- Nitrile (A) heptanoic acid N-0, 3-(3-chloro-4-isopropoxy-phenyl) 5-hexyl-[1,2,4] drink two sigma sitting 3.01 (b) 323.20 ( M+H)+

127788.doc -107- 200840567127788.doc -107- 200840567

實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法） m/z A.49 3-氣-4-異丙氧 基-节腈 (A) 4,4,4-三氟 丁酸 人 3-(3-氯-4-異丙 氧基-苯基)-5-(3,3,3-三氟-丙 基 Hl，2,4]-咢二 σ坐 2.68 (e) 334 (M-H)· A.50 3-氣-4-異丙氧 基-¥腈 (A) 曱氧基-乙 酸 3-(3-氣-4-異丙 氧基-苯基)-5-甲 氧基曱基-[1，2,4]崎二唑 2.40 (b) 283 (M+H)+ A.51 3-氯-4-異丙氧 基-节腈 (A) 曱基硫基· 乙酸 N/〇\ 人 3-(3-氣-4-異丙 氧基-苯基)-5-曱 基硫基曱基-[1，2,4?咢二唑 2.55 (b) 299 (M+H)+ A.52 3-氯-4-異丙氧 基-节腈 (A) 乙氧1基-乙 酸 人 3-(3-氯-4-異丙 氧i基-苯基)-5-乙 氧基甲基-[1，2,4]嘮二唑 2.51 (b) 297 (M+H)+ A.53 3-氯-4-異丙乳 基-节腈 (A) (2·曱氧基-乙氧基)-乙 酸 3-(3-氯-4-異丙 氧基-苯基)-5-(2-曱氧基-乙氧 基曱基)-[1，2,4]哼二唑 235 (b) 327 (M+H)+ A.54 3-氣-4-異丙氧 基-苄腈 (A) 四氮°夫喃-2-甲酸 N^°v 广、 3-(3-氯-4-異丙 氧基-苯基)-5-(四氮-咬°南-2-基)-[1，2,4] 口咢二 口坐 2.37 (e) 308 (M-H)' A.55 3-氯-4-異丙氧 基-节腈 (A) 四氮ϋ夫喃-3-甲酸 3-(3-氯-4-異丙 氧基-苯基)-5-(四氮-咬喃-3-基)-[1，2,4]哼二 口坐 2.43 (b) 309 (M+H)+ A.56 3-氯-4-異丙氧 基哼腈 (A) 環丙烷甲酸 jOO^ 3-(3-氯-4-異丙 氧基-苯基)-5-環 丙基-[1，2,4]喝 二口坐 ‘ 2.61 (b) 279 (M+H)+ 127788.doc 108- 200840567Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.49 3-ox-4-isopropoxy- nitrite (A) 4,4,4-trifluorobutyric acid 3-(3-Chloro-4-isopropoxy-phenyl)-5-(3,3,3-trifluoro-propyl Hl,2,4]-indole sigma sitting 2.68 (e) 334 (MH A.50 3-oxo-4-isopropoxy-acetonitrile (A) methoxy-acetic acid 3-(3-a-4-isopropoxy-phenyl)-5-methoxyindole Base-[1,2,4] Soxadiazole 2.40 (b) 283 (M+H)+ A.51 3-Chloro-4-isopropoxy- nitrite (A) Mercaptothio-acetic acid N/ 〇\ 人 3-(3-Actyl-4-isopropoxy-phenyl)-5-mercaptothioindolyl-[1,2,4?oxadiazole 2.55 (b) 299 (M+H) + A.52 3-Chloro-4-isopropoxy-n-nitrile (A) Ethoxy-1-yl-acetic acid human 3-(3-chloro-4-isopropoxy i-phenyl)-5-ethoxy Methyl-[1,2,4]oxadiazole 2.51 (b) 297 (M+H)+ A.53 3-chloro-4-isopropyllacyl-n-butyronitrile (A) (2. -ethoxy)-(3-chloro-4-isopropoxy-phenyl)-5-(2-decyloxy-ethoxyindolyl)-[1,2,4]fluorene Azole 235 (b) 327 (M+H)+ A.54 3-oxo-4-isopropoxy-benzonitrile (A) tetrazine-pentan-2-carboxylic acid N^°v broad, 3-(3 -chloro-4-isopropoxy-phenyl)-5-(four Nitrogen-bite °Nan-2-yl)-[1,2,4] Two mouths sitting 2.37 (e) 308 (MH)' A.55 3-chloro-4-isopropoxy- nitrite (A Tetrazofuran-3-carboxylic acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(tetraz-carbazyl-3-yl)-[1,2,4]哼Two sit at 2.43 (b) 309 (M+H) + A.56 3-chloro-4-isopropoxycarbonitrile (A) cyclopropanecarboxylic acid jOO^ 3-(3-chloro-4-isopropoxy -Phenyl)-5-cyclopropyl-[1,2,4] drink two sitting ' 2.61 (b) 279 (M+H)+ 127788.doc 108- 200840567

實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法） m/z A.57 3-氣-4-異丙氧 基-节腈 (A) 環丁烷曱酸 3-(3-氯-4-異丙 氧基-苯基)-5·環 丁基-[1，2,4]咩 二吐 2.75 (b) 293 (M+H)+ A.58 3-氣-4-異丙氧 基-节腈 (A) 環戊烷曱酸 3-(3-氯-4-異丙 氧基-苯基)-5·環 戊基-[1,2,4]咩 二峻 2.86 (b) 307 (M+H)+ A.59 3-氯-4-異丙氧 基-节腈 (A) 環戊基-乙 酸 Ν—〇\ 3-(3-氯-4-異丙 乳基-苯基)-5-¾ 戊基曱基-[1，2,4]崎二唑 2.95 (b) 321 (M+H)+ A.60 3-氯-4-異丙氧 基-节腈 (A) 環己烷曱酸 3-(3-氯-4-異丙 氧基-苯基)-5-環 己基-[1，2,4]吟 二口坐 2.96 (b) 321 (M+H)+ A.61 3-氯-4-異丙乳 基·节腈 (A) 環己基-乙 酸 Ν/〇\ 3-(3-氯-4-異丙 氧基-苯基)-5-環 己基曱基_ [1，2,4]哼二唑 3.04(b) 335 (M+H)+ A.62 3-氣-4-異丙氧 基-节腈 (A) 1-曱基-環丙 烷曱酸 3-(3-氯-4-異丙 氧基-苯基)-5· (1-曱基-環丙 基)-[1，2,4]哼二 口坐 2.76 (b) 293 (M+H)+ A.63 3-氯-4-異丙乳 基-节腈 (A) 2-曱基-環丙 烷曱酸 3-(3-氯-4-異丙 氧基-苯基)-5-(2-甲基-¾丙 基)-[1，2,4] 口咢二 口坐 2.73 (b) 293 (M+H)+ A.64 3-氣-4-異丙乳 基-节腈 (A) 3 -乙氧基-汚 酸 3-(3-氯-4-異丙 氧基-苯基)-5-(2-乙氧基-乙 基)-[1，2,4]哼二 口坐 2.53 (b) 311(M+H)+ 127788.doc 109- 200840567 實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法) m/z A.65 3-氯-4-異丙氧 基-节腈 (A) (S)-5-側氧 基比洛咬- 2胃甲酸 N，〇 Chin 〔S)-5-[3-(3-氣-4- 異丙氧基-苯 基)-[1，2,4]吟二 °坐-5-基]-°比°各 啶-2-酮 1.88(e) 321 (M-H)· A.66 3-氯-4-異丙氧 基腈 (A) ⑻-5-側氧 基-D比嘻咬-2-曱酸 N，〇 八 Chiral (R)-5-[3-(3-氯-4-異丙氧基-苯 基)-[1，2,4]喝二 σ坐-5·基]-σ比嘻 啶-2-酮 1.90 (e) 321 (M-H)· A.67 3-氯-4-異丙氧 基-节腈 ㈧ 苄基氧基-乙酸 Ν^0\ 5-苄基氧基曱 基-3-(3-氯-4-異 丙氣基-苯基)-[1，2,4]噚二唑 2.70 (b) 359 (M+H)+ A.68 3-氯-4-異丙氧 基-节腈 (A) 1-苯基-環戊 烷曱酸 3-(3-氯-4-異丙 氧基-苯基)-5-(1-苯基-環丙 基)-[1，2,4]吟二 吐 2.88 (b) 355 (M+H)+ A.69 3-氯-4-異丙氧 基4腈 (A) (S)-2-苯基- 丁酸 \ Chiral 3-(3-氯-4-異丙 氧基-苯基)-5-((S)-l-苯基-丙 基Hl，2,4?咢二 峻 2.94 (b) 357 (M+H)+ A.70 3-氯-4-異丙氧 基-¥腈 (A) 4-苯基-丁酸 Ν^°ν 3-(3-氯-4-異丙 氧基-苯基)-5-(3-苯基-丙基)-[1，2,4]呤二唑 2.88(b) 357 (M+H)+ A.71 3-氮-4-異丙氧 基腈 (A) (R)-曱氧基-苯基-乙酸 \ Chiral Ν 一 〇\ Ο 3-(3-氯-4-異丙 氧基-苯基)-5-((R)-甲氧基-苯 基-甲基)-[1，2,4]嘮二唑 2.72 (b) 359 (M+H)+ A.72 3-氣-4-異丙氧 基碎腈 (A) (S)-甲氧基-苯基-乙酸 \ Chiral Ν —〇、 JD 3-(3-氯-4-異丙 氧基-苯基)-5-(⑸-曱氧基-苯 基-甲基)-[1，2,4]噚二唑 2.72 (b) 359 (M+H)+ 127788.doc -110- 200840567 實例 編號 腈前驅物 酸或醢氣 產物 名稱 Rt/min (方法） m/z A.73 3-氯-4·異丙氧 基-节腈 (Α) 3-苯氧基-丙 酸 3-(3-氯-4·異丙 氧基-苯基)-5-(2-苯氧基-乙 基)-[1，2,4]呤二 嗤 2.72 ⑻ 358 (M-H)· A.74 3-氯-4-異丙氧 基-节腈 (Α) [(呋喃-2-羰 基)-胺基]-乙酸 呋喃-2-曱酸[3-(3-氯-4-異丙氧 基-苯基)-:1，2,4]噚二唑-5-基曱基]-醯胺 2.20(b) 362 (M+H)+ A.75 3-氯-4-異丙氧 基·节腈 (Α) 4-噻吩-2-基-丁酸 3-(3-氯-4-異丙 氧基-苯基)-5-(3-口塞吩-2-基-丙 基)-[1，2,4]喝二 〇坐 2.84 (b) 363 (M+H)+ A.76 3-氣-4-異丙氧 基-节腈 (Α) 1-乙酿基-派 咬-4-曱酸 丄^κκ H4-[3-(3-氣-4· 異丙氧基-苯 基)-[1，2,4]噚二 嗤-5-基]-派咬-1-基}-乙酉同 2.26 (b) 364 (M+H)+ A.77 3-氣-4·異丙氧 基腈 (Α) (3,5-二氣-苯 基)-乙酸 F 3-(3-氯-4-異丙 氧基-苯基)-5-(3,5-二氟-苄基)-[1，2,4]噚二唑 2.75 (b) 365 (M+H)+ A.78 3-氣-4-異丙氧 基·节腈 (Α) 4-側氧基-4- 苯基·丁酸 3-[3-(3-氯-4-異 丙氧基·苯基)-[1，2,4]今二唑-5-基]-1-苯基-丙 烧-1-嗣 2.64 (b) 371 (M+H)+ Α·79 3-氯-4-異丙氧 基-节腈 (Α) 4-苯氧基-丁 酸 3-(3-氣-4-異丙 氧基-苯基)-5-(3-苯氧基_丙 基)-[1，2,4]噚二 嗤 2.79 (b) 373 (M+H)+ Α.80 3-氣-4-異丙氧 基-节腈 (Α) 4-侧氧基-4-噻吩-2-基- 丁酸 3-[3-(3-氯冰異 丙氧基-苯基)-[1，2,4]今二嗤-5· 基]-1 ·σ塞吩-2-基-丙姨》-1 -明 • 2.57 (b) 377 (M+H)+ -Ill - 127788.doc 200840567 實例 編號 腈前駆物 酸或醢氣 產物 名稱 Rt/min (方法） m/z A.81 3-氯-4-異丙氧 基腈 (A) 4-苯基胺曱 醯基-丁酸 。6 4-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]-Ν-苯基-丁 醯胺 2.45 (b) 400 (M+H)+ A.82 3-氯-4-異丙氧 基-节腈 (A) (甲苯-4-確 驢基胺基)-乙酸 Ν-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基曱基]-4-曱基- 苯石黃醯胺 2.44 (b) 422 (M+H)+ A.83 3-氯-4-異丙氧 基-节腈 (A) 4-乙醯基-苯 曱酸 1-{4-[3-(3-氯-4-異丙氧基-苯 基)-[1，2,4]吟二 峻-5-基]-苯基}-乙酮 2.72 (b) 357 (M+H)+ A.84 3-氯-4-異丙氧 基-¥腈 (A) 4-二乙胺基_ 苯甲酸 XI/叫 HO^^O {4-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]嘮二唑-5-基]-苯基}_二乙 基-胺;與三氟乙 酸之化合物 3.00 (b) 386 (M+H)+ A.85 3-氯-4-異丙氧 基-节腈 (A) 丙酸 N—0\ 丄)0^ 3-(3-氣-4-異丙 氧基-苯基&gt;5-乙 基-[1，2,4]噚二 口坐 2.55(b) 267 (M+H)+ A.86 3-氯-4_異丙氧 基-节腈 (A) 丁酸 3-(3-氯-4-異丙 氧基-苯基)-5-丙 基-[1，2,4]哼二 口坐 2.69 (b) 281 (M+H)+ A.87 3-氯-4-異丙氧 基-节腈 (A) 異丁酸 Ν 一 0\ / 3-(3-氯-4-異丙 氧基-苯基)-5·異 丙基-[1，2,4] 口咢 二唆 2.70 (b) 281 (M+H)+ A.88 3-氯-4-異丙氣 基-节腈 ㈧ 戊酸 Ν^°ν 5-丁基-3-(3-氣- 14-異丙氧基-苯 基)-[1，2,4]哼二 T7坐 2.81 (b) 295 (M+H)+ 127788.doc -112- 200840567Example No. Nitrile Precursor Acid or Helium Product Name Rt/min (Method) m/z A.57 3-Gas-4-Isopropoxy-N-Nitrile (A) Cyclobutane Citrate 3-(3-Chlorine -4-isopropoxy-phenyl)-5.cyclobutyl-[1,2,4]indole 2.75 (b) 293 (M+H)+ A.58 3-ox-4-isopropyl Oxy-n-butyronitrile (A) cyclopentane decanoic acid 3-(3-chloro-4-isopropoxy-phenyl)-5·cyclopentyl-[1,2,4] fluorene 2.86 (b ) 307 (M+H)+ A.59 3-Chloro-4-isopropoxy- nitrite (A) Cyclopentyl-acetic acid hydrazine-〇\ 3-(3-chloro-4-isopropyllacyl- Phenyl)-5-3⁄4 pentyl decyl-[1,2,4] soxadiazole 2.95 (b) 321 (M+H) + A.60 3-chloro-4-isopropoxy- nitrite ( A) 3-(3-chloro-4-isopropoxy-phenyl)-5-cyclohexyl-[1,2,4] fluorene cyclohexane citrate sits 2.96 (b) 321 (M+H + A.61 3-Chloro-4-isopropyllactyl-n-nitrile (A) Cyclohexyl-acetic acid hydrazine/hydrazine\ 3-(3-chloro-4-isopropoxy-phenyl)-5-ring Hexyl fluorenyl _ [1,2,4]oxadiazole 3.04(b) 335 (M+H)+ A.62 3-oxo-4-isopropoxy- nitrite (A) 1-indenyl-ring Propane decanoic acid 3-(3-chloro-4-isopropoxy-phenyl)-5·(1-indolyl-cyclopropyl)-[1,2,4]哼 two sitting 2.76 (b) 293 (M+H)+ A.63 3-chloro-4 -isopropyl isopropyl- nitrite (A) 2-mercapto-cyclopropane decanoic acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(2-methyl-3⁄4 propyl) -[1,2,4] Two mouthfuls sitting 2.73 (b) 293 (M+H)+ A.64 3-gas-4-isopropyllacyl-nodal nitrile (A) 3-ethoxy-stain Acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(2-ethoxy-ethyl)-[1,2,4]哼 two sitting 2.53 (b) 311 (M +H)+ 127788.doc 109- 200840567 Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.65 3-chloro-4-isopropoxy-quinone (A) ( S)-5-Sideoxybilobitone-2 Gastrin N, 〇Chin [S)-5-[3-(3-Gas-4-isopropoxy-phenyl)-[1,2,4吟2° sit-5-yl]-° ratio ° pyridine-2-one 1.88(e) 321 (MH)· A.66 3-chloro-4-isopropoxy nitrile (A) (8)-5- Side oxy-D is more than bite -2-nonanoic acid N, 〇8 Chiral (R)-5-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4] Drinking two sigma -5 -yl]-σ-pyridin-2-one 1.90 (e) 321 (MH) · A.67 3-chloro-4-isopropoxy- nitrite (VIII) benzyloxy-acetic acid Ν^0\ 5-benzyloxyindolyl-3-(3-chloro-4-isopropyl-carbo-phenyl)-[1,2,4]oxadiazole 2.70 (b) 359 (M+H ) + A.68 3-chloro-4-isopropyl Base-nodal nitrile (A) 1-phenyl-cyclopentane decanoic acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(1-phenyl-cyclopropyl)-[1 ,2,4]吟二吐 2.88 (b) 355 (M+H)+ A.69 3-chloro-4-isopropoxy 4 nitrile (A) (S)-2-phenyl-butyric acid \ Chiral 3-(3-Chloro-4-isopropoxy-phenyl)-5-((S)-l-phenyl-propyl Hl,2,4?咢二峻 2.94 (b) 357 (M+H + A.70 3-chloro-4-isopropoxy-acetonitrile (A) 4-phenyl-butyric acid Ν^°ν 3-(3-chloro-4-isopropoxy-phenyl)- 5-(3-Phenyl-propyl)-[1,2,4]oxadiazole 2.88(b) 357 (M+H)+ A.71 3-nitro-4-isopropoxycarbonitrile (A) (R)-decyloxy-phenyl-acetic acid \ Chiral Ν 〇 Ο 3-(3-chloro-4-isopropoxy-phenyl)-5-((R)-methoxy-phenyl -methyl)-[1,2,4]oxadiazole 2.72 (b) 359 (M+H)+ A.72 3-ox-4-isopropoxyacetonitrile (A) (S)-methoxy -Phenyl-acetic acid\Chiral Ν-〇, JD 3-(3-chloro-4-isopropoxy-phenyl)-5-((5)-decyloxy-phenyl-methyl)-[1, 2,4]oxadiazole 2.72 (b) 359 (M+H)+ 127788.doc -110- 200840567 Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.73 3- Chloro-4·isopropoxy-quinone (Α) 3-phenoxy -3-(3-chloro-4.isopropoxy-phenyl)-5-(2-phenoxy-ethyl)-[1,2,4]fluorene dipropionate 2.72 (8) 358 (MH) · A.74 3-chloro-4-isopropoxy-quinone (Α) [(furan-2-carbonyl)-amino]-furoyl-2-furoic acid [3-(3-chloro-4- Isopropoxy-phenyl)-:1,2,4]oxadiazol-5-ylindenyl]-nonylamine 2.20(b) 362 (M+H)+ A.75 3-chloro-4-iso Propoxy quinolate (Α) 4-thiophen-2-yl-butyric acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(3-porter-2-yl- Propyl)-[1,2,4] drink two squats 2.84 (b) 363 (M+H)+ A.76 3-oxo-4-isopropoxy-nickel (Α) 1-ethyl - Pieces -4- 曱 丄 κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ κ -1-yl}-acetamidine with 2.26 (b) 364 (M+H)+ A.77 3-ox-4·isopropoxy nitrile (Α) (3,5-di-phenyl)-acetic acid F 3-(3-Chloro-4-isopropoxy-phenyl)-5-(3,5-difluoro-benzyl)-[1,2,4]oxadiazole 2.75 (b) 365 (M+ H)+ A.78 3-oxo-4-isopropoxy methoxyl (Α) 4-sided oxy-4-phenyl-butyric acid 3-[3-(3-chloro-4-isopropoxy Benzyl)-[1,2,4], oxadiazol-5-yl]-1-phenyl-propan-1-ylidene 2.64 (b) 371 (M+H)+ Α·79 3- 4-isopropoxy-n-nitrile (fluorene) 4-phenoxy-butyric acid 3-(3-vapor-4-isopropoxy-phenyl)-5-(3-phenoxy-propyl )-[1,2,4]噚二嗤2.79 (b) 373 (M+H)+ Α.80 3-oxo-4-isopropoxy-quinone (Α) 4-side oxy-4- Thiophen-2-yl-butyric acid 3-[3-(3-chloroisoisopropoxy-phenyl)-[1,2,4] quinone-5-yl]-1 σ septene-2 -基-丙姨》-1 -明• 2.57 (b) 377 (M+H)+ -Ill - 127788.doc 200840567 Example number nitrile pro-antimony acid or helium product name Rt/min (method) m/z A .81 3-Chloro-4-isopropoxy nitrile (A) 4-phenylamine mercapto-butyric acid. 6 4-[3-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-indole-phenyl-butanamine 2.45 (b) 400 (M+H)+ A.82 3-chloro-4-isopropoxy-sulfonic acid (A) (toluene-4-dedecylamino)-hydrazine acetate-[3-(3-chloro-4) -isopropoxy-phenyl)-[1,2,4]oxadiazol-5-ylindenyl]-4-mercapto-benzophenone oxime 2.44 (b) 422 (M+H)+ A .83 3-Chloro-4-isopropoxy-n-nitrile (A) 4-Ethyl-benzoic acid 1-{4-[3-(3-chloro-4-isopropoxy-phenyl) -[1,2,4]吟二峻-5-yl]-phenyl}-ethanone 2.72 (b) 357 (M+H)+ A.84 3-chloro-4-isopropoxy-acetonitrile (A) 4-diethylamino benzoic acid XI / HO ^ ^ O {4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]唠2 Zyrid-5-yl]-phenyl}-diethyl-amine; compound with trifluoroacetic acid 3.00 (b) 386 (M+H) + A.85 3-chloro-4-isopropoxy- nitrite (A) Propionate N—0\丄)0^ 3-(3-Actyl-4-isopropoxy-phenyl&gt;5-ethyl-[1,2,4]噚 two sitting 2.55 (b ) 267 (M+H)+ A.86 3-Chloro-4_isopropoxy-quinone (A) Butyric acid 3-(3-chloro-4-isopropoxy-phenyl)-5-prop Base - [1, 2, 4] 哼 two sitting 2.69 (b) 281 (M + H) + A.87 3-chloro-4-isopropoxy- nitrite (A) isobutyric acid Ν 0\ / 3-(3-chloro-4-isopropoxy-phenyl)-5.isopropyl-[1,2,4] 咢2咢 2.70 (b) 281 (M+H) + A.88 3-Chloro-4-isopropenyl-nodal nitrile (8) Valeric acid Ν^°ν 5-butyl-3-(3-aero- 14-isopropoxy-phenyl)-[1, 2,4]哼二T7 sits 2.81 (b) 295 (M+H)+ 127788.doc -112- 200840567

實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法） m/z A.89 3-氯-4-異丙氧 基-¥腈 (A) 2-曱基-丁酸 N^°v / 5-第二丁基-3_ (3-氯-4-異丙氧 基'苯基)-[1,2,4]噚二唑 2.82 (b) 295 (M+H)+ A.90 3-氣-4-異丙乳 基-节腈 (A) 3-甲基-丁酸 3-(3-氯-4-異丙 氧基-苯基)-5-異 丁基-[1，2,4]嘮 二口坐 2.80 (b) 295 (M+H)+ A.91 3-氣-4-異丙氧 基-节腈 (A) 己酸 N-^°v 3-(3-氯-4-異丙 氧基-苯基)-5-戍 基-[1，2,4妒咢二 σ坐 2.92 (b) 309 (M+H)+ A.92 3-氣-4-異丙乳 基-¥腈 (A) 4-第三丁氧 基羰基胺 基-苯曱酸 {4-[3-(3-氯冬異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]-苯基卜胺基 甲酸第三丁酯 2.90 (b) 430 (M+H)+ A.93 3-氣-4-異丙氧 基-节腈 (A) 3-氰基-苯曱 酸 Ν 3-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]-苄腈 2.71 (b) Note b A.94 3-氣-4-異丙氧 基-节腈 (A) 4-氰基-苯甲 酸 4-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]崎二唑-5-基]-节腈 2.71 (b) Note C A.95 3-氯-4-異丙氧 基-节腈 (A) 3-二曱基胺 基-苯曱酸 {3-[3-(3-氯-4-異 丙氧基-苯基)-[l，2,4] 噚二唑-5-基]-苯基}-二曱 基-胺 2.94 (b) 358 (M+H)+ A.96 3-氣-4-異丙氧 基·节腈 (A) 聯苯-4-基-乙酸 Ν^〇\ 5-Bi苯基-4-基 甲基-3·(3-氯-4-異丙氧基-苯 基)·[1，2,4] 口号二 σ坐 2.93 (b) 405 (M+H)+ 127788.doc 113- 200840567 實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法） m/z A.97 3-氯-4-異丙氧 基-节腈 (A) (4-二甲胺 基-苯基)-乙 酸 N — / {4-[3-(3-氯-4_ 異 丙氧基-苯基)-[1，2,4]嘮二唑-5-基甲基]-苯基}-二甲基-胺 2.78 (b) 372 (M+H)+ A.98 3-氣-4-異丙氧 基-节腈 (A) (4-苯氧基_ 苯基)-乙酸 3-(3-氯-4-異丙 氧基-苯基)-5-(4-苯氧基-苄 基)-[1，2,4]呤二 口坐 2.92 (b) 421 (M+H)+ A.99 3-氯-4-異丙氧 基-节腈 (A) (4-节基氧 基-苯基)-乙 酸 N—〇\ N — / 5-(4-苄基氧基-节基)-3-(3-氯-4· 異丙氧基-苯 基Hl，2,4]呤二 口坐 2.89 (b) 435 (M+H)+ A. 100 3-氯-4-異丙乳 基-节腈 (A) 秦-1-基-乙 酸 3-(3-氯-4-異丙 氧基-苯基)-5-秦-1·基曱基-[1,2,4]噚二唑 2.85 (b) 379 (M+H)+ A.101 3-氣-4-異丙氧 基-节腈 (A) 蔡-2-基-乙 酸 3-(3-氣-4-異丙 氧基·苯基)-5-条-2-基曱基-[1，2,4]呤二唑 2.87 (b) 379 (M+H)+ A.102 3-氯-4-異丙氧 基-节腈 (A) 0夫喃-2-曱酸 3-(3-氯-4-異丙 氧基-苯基)-5-咬 喃-2-基_ [1，2,4]喝二唑 2.62 (b) 305 (M+H)+ A. 103 3-氣-4-異丙氧 基-节腈 (A) 吱喃-3-甲酸 3-(3-氣-4-異丙 乳基-苯基)-5-咳 喃-3-基-[1，2,4]崎二唑 2.64(b) 305 (M+H)+ A. 104 3-氯_4-異丙氧 基-节腈 (A) 噻吩-2-曱酸 3-(3-氯-4-異丙 氧基-苯基)-5-嗟 吩-2-基-[1，2,4] 口号二口坐 2.78(b) .___ 321 (M+H)+ 127788.doc 114- 200840567 實例 編號 腈前驅物 酸或醢氣 產物 名稱 Rt/min (方法） m/z A.105 3-氯-4-異丙氧 基-苄腈（A) 嗟吩-3-曱酸 3-(3-氯-4-異丙 氧基-苯基)-5•嗟 吩-3备 [1，2,4]嘮二唑 2.75(b) 321 (M+H)+ A.106 3·氯-4-異丙氧 基-苄腈（A) 1-曱基-1H-吡咯-2-曱酸 3-(3-氣-4-異丙 氧基-苯基)-5-(1-甲基-1H-吡 °各-2-基)-[1，2,4] 口咢二唑 2.75 (b) 318(M+H)+ A. 107 3-氯-4-異丙氧 基-节腈 (A) 噻唑-4-甲酸 Ν^°\ 乂 3-(3-氯-4-異丙 氧基-苯基)-5·噻 唑-4-基-[1，2,4]呤二唑 2.42 (b) 322 (M+H)+ A.108 3-氯-4-異丙氧 基-节腈 (A) 3,5-二甲基-異巧唑冬甲 酸 ;〇〇^ 3-(3-氯-4-異丙 氧基-苯基)-5-(3,5-di曱基-異 巧唑_4·基)-[1，2,4]嘮二唑 2.72 (b) 334 (M+H)+ A. 109 3_氯-4-異丙氧 基-苄腈 (A) 5-曱基-吡 嗪-2-甲酸 2-[3-(3-氯斗異 丙氧基-苯基)-[1，2,4]口咢二唑-5-基]-5-曱基-吼唤 2.50 (b) 331 (M+H)+ A.110 3-氯-4-異丙氧 基-节腈 (A) 4-側氧基-4,5,6,7,四氫 苯弁11 夫喃-3-曱酸 .〇Λ〇 λΧΧ 3-[3-(3-氣-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]-6,7-二氫-5H-本弁σ夫喃-4-酮 2.48 (b) 373 (M+H)+ A.lll 3·氯-4-異丙氧 基-节腈 (A) 嗎琳-4-基-乙酸 N—〇\ 4-[3-(3-氯-4-異 丙氧基-苯基)_ [1，2,4]嘮二唑-5-基甲基]-嗎琳 2.70 (b) Note d A.112 3-氯-4-異丙氧 基-苄腈 (A) 3-氯-異終驗 酸 ^〇A^b 3- 氯-4-[3-(3-氯- 4- 異丙氧基-苯 基)-[1，2,4]哼二 嗤-5-基]-σ比咬 3.02 (f) 350 (M+H)+ 127788.doc -115· 200840567Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.89 3-chloro-4-isopropoxy-acetonitrile (A) 2-mercapto-butyric acid N^°v / 5-Second-butyl-3_(3-chloro-4-isopropoxy 'phenyl)-[1,2,4]oxadiazole 2.82 (b) 295 (M+H)+ A.90 3 - gas-4-isopropyllacyl-nodal nitrile (A) 3-methyl-butyric acid 3-(3-chloro-4-isopropoxy-phenyl)-5-isobutyl-[1,2 , 4] 唠 two sitting 2.80 (b) 295 (M+H) + A.91 3-gas-4-isopropoxy- nitrite (A) hexanoic acid N-^°v 3-(3-chlorine -4-Isopropoxy-phenyl)-5-mercapto-[1,2,4妒咢2 σ sitting 2.92 (b) 309 (M+H)+ A.92 3-Q4-isopropyl Milk-based nitrile (A) 4-tert-butoxycarbonylamino-benzoic acid {4-[3-(3-chloroisopropoxy-phenyl)-[1,2,4]呤Tert-butyl-5-yl]-phenyl-p-aminocarbamic acid tert-butyl ester 2.90 (b) 430 (M+H)+ A.93 3-oxo-4-isopropoxy- nitrite (A) 3- Cyano-benzoquinone hydrazide 3-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile 2.71 (b) Note b A.94 3-oxo-4-isopropoxy- nitrite (A) 4-cyano-benzoic acid 4-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4] Soxadiazole-5-yl]-mercaptonitrile 2.71 (b) Note C A.95 3-Chloro-4-isopropoxy-n-nitrile (A) 3-didecylamino-benzoic acid {3-[3-(3-chloro-4-isopropoxy-phenyl) )-[l,2,4]oxadiazol-5-yl]-phenyl}-didecyl-amine 2.94 (b) 358 (M+H)+ A.96 3-ox-4-isopropoxy Base nitrite (A) biphenyl-4-yl-acetic acid Ν^〇\ 5-Biphenyl-4-ylmethyl-3·(3-chloro-4-isopropoxy-phenyl)·[ 1,2,4] Slogan sigma sitting 2.93 (b) 405 (M+H)+ 127788.doc 113- 200840567 Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.97 3-Chloro-4-isopropoxy-cyanocarbonitrile (A) (4-dimethylamino-phenyl)-acetic acid N — / {4-[3-(3-chloro-4_isopropoxy-benzene) Base)-[1,2,4]oxadiazol-5-ylmethyl]-phenyl}-dimethyl-amine 2.78 (b) 372 (M+H)+ A.98 3- gas-4- Isopropoxy-n-nitrile (A) (4-phenoxy-phenyl)-acetic acid 3-(3-chloro-4-isopropoxy-phenyl)-5-(4-phenoxy-benzyl Base)-[1,2,4]呤2 sitting 2.92 (b) 421 (M+H)+ A.99 3-chloro-4-isopropoxy- nitrite (A) (4-gangyl oxygen) Benzyl-phenyl)-acetic acid N-〇\ N — / 5-(4-benzyloxy-benzyl)-3-(3-chloro-4·isopropoxy-phenyl Hl,2,4] Squatting 2.89 (b) 435 (M+H) + A. 100 3-chloro-4-isopropyllacyl-nodal nitrile (A) Qin-1-yl-acetic acid 3-(3-chloro-4-isopropoxy-phenyl)-5- Qin- 1·ylmercapto-[1,2,4]oxadiazole 2.85 (b) 379 (M+H)+ A.101 3-ox-4-isopropoxy-quinone (A) Cai-2- 3-acetic acid 3-(3-, 4-isopropoxy-phenyl)-5-yl-2-ylindolyl-[1,2,4]oxadiazole 2.87 (b) 379 (M+H ) + A.102 3-Chloro-4-isopropoxy-n-nitrile (A) 0-propan-2-indole 3-(3-chloro-4-isopropoxy-phenyl)-5-bit -2--2-yl _ [1,2,4] drink diazole 2.62 (b) 305 (M+H)+ A. 103 3-ox-4-isopropoxy- nitrite (A) 吱 -3 -3 -carboxylic acid 3-(3-Ga-4-isopropyllacyl-phenyl)-5-c-butyl-3-yl-[1,2,4] Soxadiazole 2.64(b) 305 (M+H)+ A. 104 3-Chloro-4-isopropoxy-n-nitrile (A) Thiophene-2-decanoic acid 3-(3-chloro-4-isopropoxy-phenyl)-5-nonyl-2- Base-[1,2,4] Slogan two sitting 2.78(b) .___ 321 (M+H)+ 127788.doc 114- 200840567 Example number nitrile precursor acid or helium product name Rt/min (method) m /z A.105 3-Chloro-4-isopropoxy-benzonitrile (A) 3-(3-chloro-4-isopropoxy-phenyl)-5• porphin -3 preparation [1,2,4]oxadiazole 2.75(b) 321 (M+H)+ A.106 3·Chloro-4-isopropoxy-benzonitrile (A) 1-Mercapto-1H-pyrrole-2-decanoic acid 3-(3-Ga-4-isopropoxy-phenyl)- 5-(1-methyl-1H-pyridyl-2-yl)-[1,2,4] Oroxadiazole 2.75 (b) 318(M+H)+ A. 107 3-chloro-4- Isopropoxy-knifeonitrile (A) Thiazole-4-carboxylic acid Ν^° 乂3-(3-chloro-4-isopropoxy-phenyl)-5·thiazol-4-yl-[1,2 , 4] oxadiazole 2.42 (b) 322 (M+H) + A.108 3-chloro-4-isopropoxy- nitrite (A) 3,5-dimethyl-norzoazole toluic acid; 〇〇^ 3-(3-Chloro-4-isopropoxy-phenyl)-5-(3,5-diindolyl-isoxazole_4·yl)-[1,2,4]唠二Azole 2.72 (b) 334 (M+H)+ A. 109 3-chloro-4-isopropoxy-benzonitrile (A) 5-mercapto-pyrazine-2-carboxylic acid 2-[3-(3- Chloropipeisopropoxy-phenyl)-[1,2,4]oxazolidine-5-yl]-5-mercapto-purine 2.50 (b) 331 (M+H)+ A.110 3 -Chloro-4-isopropoxy-cyanocarbonitrile (A) 4-Alkyloxy-4,5,6,7,tetrahydrophenylhydrazine 11 Furan-3-decanoic acid. 〇Λ〇λΧΧ 3-[3 -(3- gas-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6,7-dihydro-5H-benzazole 夫-4- Ketone 2.48 (b) 373 (M+H)+ A.lll 3·Chloro-4-isopropoxy- nitrite (A) 琳琳-4-yl-acetic acid N-〇\ 4-[3-(3 -chlorine -4-Isopropoxy-phenyl)_[1,2,4]oxadiazol-5-ylmethyl]-Merline 2.70 (b) Note d A.112 3-chloro-4-isopropoxy Base-benzonitrile (A) 3-chloro-iso-final acid 〇A^b 3-chloro-4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2, 4]哼二嗤-5-yl]-σ ratio bite 3.02 (f) 350 (M+H)+ 127788.doc -115· 200840567

實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法） m/z A.113 3-氯-4-異丙氧 基-节腈 (A) 3-氯-苯曱酸 χχ/Ν 3-(3-氣4-異丙 氧基-苯基)-5-(3-氣-苯基)-[1，2,4] 口咢二唑 3.22(f) 349 (M+H)+ A.114 3-氯-4-異丙氧 基-节腈 (A) 3-氟·異菸鹼 酸 λΧγ1^ 4-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]噚二唑-5-基]-3-1^比咬 2.93 (f) 334 (M+H)+ A.115 3-氯-4-異丙氧 基-节腈 (A) 2-氯-異於驗 酸 2-氣-4-[3·(3-氯-4-異丙氧基-苯 基Ml，2,4]噚二 峻-5-基]-吼咬 3.05 (f) 351 (M+H)+ A.116 3-氯-4-異丙氧 基-节腈 (A) 2-氟-異於鹼 酸 4-[3-(3·氣-4-異 丙氧基-苯基)-[1，2,4]4二唑-5-基]-2-氟-β比咬 2.95 (f) 334 (M+H)+ A.117 3-氯-4-異丙氧 基-苄腈 (A) 啥琳-4-曱酸 4-[3-(3-氯-4-異 丙氧基-苯基)-[1，2,4]呤二唑-5-基]-啥啉 3 .27 (f) 366 (M+H)+ A.118 3-氯-4-異丙氧 基-节腈 (A) 2,6-二氯-異 於驗酸 Χχ/Ν: 2,6-二氣-4·[3-(3-氯-4-異丙氧 基-苯基)-[1，2,4] 口咢二唑-5-基]-吡咬 3.18(f) Note e A.119 3-氣-4-異丙氧 基-5-甲氧基- 苄腈 苯甲醯氯 /〇 3-(3-氯-4-異丙 氧基-5-甲氧基-苯基)-5-苯基-[1，2,4]呤二唑 3.17(b) 345 (M+H)+ A. 120 3-氯-4-異丙氧 基-5-甲氧基- 苄腈 異菸鹼醯氯 --- 4-[3-(3-氯-4-異 丙氧基-5-甲氧 基-苯基)-[1，2,4]噚二唑-5-基]-β比咬 3.14(b) 346 (M+H)+ I27788.doc -116- 200840567Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.113 3-chloro-4-isopropoxy- nitrite (A) 3-chloro-benzoic acid hydrazine/hydrazine 3 -(3- gas 4-isopropoxy-phenyl)-5-(3-a-phenyl)-[1,2,4] oxadiazole 3.22(f) 349 (M+H)+ A .114 3-chloro-4-isopropoxy-quinone (A) 3-fluoro-isonicotinic acid λΧγ1^ 4-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4]oxadiazol-5-yl]-3-1^ bite 2.93 (f) 334 (M+H)+ A.115 3-chloro-4-isopropoxy- nitrite (A 2-Chloro-isolated acid 2-gas-4-[3·(3-chloro-4-isopropoxy-phenyl Ml,2,4]噚二峻-5-yl]-bite 3.05 (f) 351 (M+H)+ A.116 3-chloro-4-isopropoxy-quinone (A) 2-fluoro-iso-alkali 4-[3-(3·gas-4-iso) Propoxy-phenyl)-[1,2,4]4diazol-5-yl]-2-fluoro-β ratio bite 2.95 (f) 334 (M+H)+ A.117 3-chloro-4 -isopropoxy-benzonitrile (A) 4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazole- 5-yl]-porphyrin 3.27 (f) 366 (M+H)+ A.118 3-chloro-4-isopropoxy- nitrite (A) 2,6-dichloro-isolated acid Χχ/Ν: 2,6-diqi-4·[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4] oxadiazole-5 -基]-Pyridine bite 3.18(f) Note e A.119 3-Actyl-4-isopropoxy-5-methoxy-benzonitrile benzamidine chloride/〇3-(3-chloro-4-iso Propoxy-5-methoxy-phenyl)-5-phenyl-[1,2,4]oxadiazole 3.17(b) 345 (M+H)+ A. 120 3-chloro-4-iso Propoxy-5-methoxy-benzonitrile isonicotinium chloride 4- 4-(3-chloro-4-isopropoxy-5-methoxy-phenyl)-[1, 2,4]oxadiazol-5-yl]-β ratio bite 3.14(b) 346 (M+H)+ I27788.doc -116- 200840567

實例 編號 腈前驅物 酸或醯氯 產物 名稱 Rt/min (方法） m/z A.121 6-曱氧基-於驗 腈 苯甲醯氣 Μ〆0、 2-甲氧基-5-(5- 苯基-[1，2,4]噚 二ϋ坐-3-基)-ϋ比咬 2.28 (b) 254 (M+H)+ A. 122 6-(2,2,2-三氟-乙氧基)-於鹼 腈 異於鹼醯氣 Ν-^°ν ρ jQ^n/&gt;^Gn F 5-(5-°比咬~4-基-[1，2,4]噚二唑各 基)-2-(2,2,2-三 氟-乙氧基)-°比 啶 2.81 (b) 323 (M+H)+ A.123 6-(2,2,2-三氟· 乙乳基)-於驗 腈 苯甲醯氯 Ν^°\ ρ F 5-(5-苯基-[l，2,4]哼二唑-3-基)-2-(2,2,2-三 it-乙氧基)-0比 啶 2.95 (b) 322 (M+H)+ A.124 6-(2,2,2-三氟-乙氧基)-菸鹼 腈 3-氯-異於驗 醯氣 (F) F 5-(3-氯吡啶-4-基)-3-(6-(2,2,2-三氟乙氧基户比 咬-3-基)-1，2,4-ρ号二咬 2.46 (b) 357 (M+H)+ A.125 6-(2,2,2-三氟-乙乳基)-於驗 腈 3-曱基-異菸 驗醯氯 (F) F 5-〇曱基吡啶-4-基)-3-(6- (2,2,2-三氟乙氧 基户比咬-^-基)-1，2,4-哼二唑 2.96(b) 337 (M+H)+ A.126 4-第三丁基-苄 腈 2-曱基-苯曱 醢氣 3-(4-第三丁基-苯基)-5-鄰-曱苯 基-[1，2,4]噚二 〇坐 3.46(b) 293 (M+H)+ A.127 3-氣-4-曱基_ 苄腈 2-曱基-苯曱 醯氯 3-(3-氣-4-曱基-苯基)-5-鄰-甲苯 基-[1，2,4]吟二 σ坐 3.40 (b) 285 (M+H)+ A.128 4-乙基-苄腈 2-曱基-苯甲 酿氯 3-(4·乙基-苯 基)-5-鄰-甲苯 基-[1，2,4]哼二 σ坐 3.39 (b) 265 (M+H)+ 127788.doc 117- 200840567Example number nitrile precursor acid or hydrazine chloride product name Rt/min (method) m/z A.121 6-decyloxy-in the nitrile benzophenone gas oxime 0, 2-methoxy-5-(5 - Phenyl-[1,2,4]噚二ϋ坐-3-yl)-ϋ比 bit 2.28 (b) 254 (M+H)+ A. 122 6-(2,2,2-trifluoro- Ethoxyl)--the alkali nitrile is different from the base 醯-^°ν ρ jQ^n/&gt;^Gn F 5-(5-° ratio bite ~4-base-[1,2,4]噚二Oxazolyl)-2-(2,2,2-trifluoro-ethoxy)-pyridyl 2.81 (b) 323 (M+H)+ A.123 6-(2,2,2-trifluoro · 乙乳基)--Acid nitrile benzoquinone chlorohydrazine^°\ ρ F 5-(5-phenyl-[l,2,4]oxadiazol-3-yl)-2-(2,2, 2-tri-it-ethoxy)-0-pyridine 2.95 (b) 322 (M+H)+ A.124 6-(2,2,2-trifluoro-ethoxy)-nicotinonitrile 3-chloro - Different from the test for helium (F) F 5-(3-chloropyridin-4-yl)-3-(6-(2,2,2-trifluoroethoxybenzil-3-yl)-1 , 2,4-ρ two bite 2.46 (b) 357 (M+H) + A.125 6-(2,2,2-trifluoro-ethyl lactyl)-in the nitrile 3-mercapto-isohalide Chlorinated (F) F 5-pyridylpyridin-4-yl)-3-(6-(2,2,2-trifluoroethoxy-bito-^-yl)-1,2,4 -oxadiazole 2.96(b) 337 (M+H)+ A.126 4-tert-butyl-benzonitrile 2-mercapto-benzoquinone 3-(4- Tributyl-phenyl)-5-o-indolephenyl-[1,2,4]噚二〇坐 3.46(b) 293 (M+H)+ A.127 3-气-4-曱基_ Benzonitrile 2-mercapto-benzoquinone 3-(3- gas-4-mercapto-phenyl)-5-o-tolyl-[1,2,4]吟 sigma sitting 3.40 (b) 285 (M+H)+ A.128 4-ethyl-benzonitrile 2-mercapto-benzyl chloro-3-(4·ethyl-phenyl)-5-o-tolyl-[1,2,4 ]哼二σ坐 3.39 (b) 265 (M+H)+ 127788.doc 117- 200840567

實例 編號 腈前驅物 酸或醢氣 產物 名稱 Rt/inin (方法） m/z A. 129 4-丁基-苄腈 2-甲基-苯曱 醯氯 3-(4-丁 基-苯 基)-5-鄰-曱苯 基-[1，2,4衿二 σ坐 3.55 (b) 293 (M+H)+ A.130 4-異丙基-节猜 2-曱基-苯甲 醯氯 3-(4-異丙基-苯 基)-5-鄰-甲苯 基-[1，2,4]噚二 口坐 3.44 (b) 279 (M+H)+ A.131 苄腈 異於鹼酸氯 4-(3-苯基-[l，2,4]嘮二唑-5-基)·σ比咬 2.48 (f) 223 (M+H)+ A.132 3-氯-苄腈 異於鹼醯氯 N,0\ c'x^n/&gt;^^n 4-[3-(3-氣-苯 基)-[1，2,4]噚二 °坐-5-基]-σ比。定 2.75 (f) 258 (M+H)+ A. 133 4-羥基-苄腈 異菸鹼醯氯 4-(5-°比°定-4-基-[1，2,4]噚二唑-3-基)-苯酚 1.95 (f) 240 (M+H)+ A.134 苯并呋喃-5-曱 腈 2-曱基-苯曱 醢氯 3-苯弁°夫°南-5-基-5-鄰-曱苯基-[1，2,4]噚二唑 3.83 (a) 277 (M+H)+ A.135 4-甲氧基各三 氟曱基-苄腈 2-甲基-苯曱 醯氯 3-(4-曱氧基-3-三氟曱基-苯 基)-5-鄰-曱苯 基-[1，2,4] 口咢二 口坐 3.31 (f) 335 (M+H)+ A.136 聯苯-4-甲腈 2-曱基_苯甲 醯氯 3-聯苯-4-基-5- 鄰-甲苯基-[1，2,4]呤二唑 3.38(f) 313 (M+H)+ 127788.doc 118- 200840567 實例 編號 腈前驅物 酸或醢氯 產物 名稱 Rt/min (方法） m/z A.137 3-氯-4-異丙氧 基苄腈 （A) 2斗二氯-苯 甲醯氯(F) CI 乂^&gt;5-, 3-(3-氯-4-異丙 氧基-苯基)-5胃 〔2,4-二氣-苯基)-[1，2,4] 口号二唑 3.48 (f) 385 (M+H)+ A.138 3 -氣-4-¾丙基 曱氧基苄腈 (B) 4-胺基-2-氣 苯甲酸 CI Cl 3-氯斗(3-(3-氯-4-異丙氧基苯 基)-1，2,4·-号二 唑-5-基)苯胺 364.09 (M+H)+ 3.08(c) A.139 3-氣-4-¾丙基 曱氧基苄腈 (B) 1-曱基-1H-吡唑-5-曱酸 η \ xx/w 3-(3-氣-4-異丙 氧基苯基)-5-(1- 曱基-m-«比口坐-5,基)-1，2,4-口亏二 TI坐 319.25 (M+H)+ 3.08(a) A.140 3 -氣-4-¾丙基 甲氧基苄腈 (B) 1-異丙基吲 D朵琳-4-曱酸 Cl 3-(3-氣-4-異丙 氧基苯基)-5-(1-異丙基-ΙΗ-吲 哚-4-基)-1，2,4- 口号二嗤 396.22 (M+H)+ 2.40 (c) A.141 3 -鼠-4-¾丙基 曱氧基苄腈 (B) 6-漠於驗酸 5-(6-漠°比咬-3-基)-3 -(3 -氣-4-異 丙氧基苯基)-1,2,4-吟二唑 396.03 (M+H)+ 3.99 (a) A.142 3-氯-4-¾丙基 甲氧基苄腈 (B) 4-(1-氰基環 丙基)苯甲 酸 1-(4-(3-(3-氯-4-異丙氧基苯基)-1，2,4-噚二唑-5-基)苯基)環丙烧 甲腈 380.43 (M+H)+ 3.19(c) A. 143 3-氯冰環丙基 曱氧基苄腈 (B) 6-溴菸鹼醯 氯 又/ 3-(3-氯-4-異丙 氧基苯基)-5-(6-氣0比咬-3-基)-1，2,4-呤二唑 350.08 (M+H)+ 3.92 (a) A. 144 3 -氣-4-¾丙基 曱氧基苄腈 (B) 1-異丙基吲 哚啉曱酸 人 Cl 3-(3-氣-4-異丙 氧基苯基)-5-( 1 · 異丙基吲哚淋-4-基)-1，2,4-吟二 口坐 398.20 (M+H)+ 3.56(c) 127788.doc -119- 200840567 實例 編號 腈前驅物 酸或醯氣 產物 名稱 Rt/min (方法） m/z A.145 3-氯-4-環丙基 曱氧基苄腈 (B) 1-(2,4-二氯 苯基)環丙 烷甲酸 hr0、h&gt; Cl 3-(3-氯-4·異丙 氧基苯基)-5-(1-(2,4-二氯苯基） 環丙基)·1，2,4- ，号二口坐 425,04 (M+H)+ 3.48 (c) A.146 3-氣-4-¾丙基 曱氧基苄腈 (B) 4-(°比咬-4-基)丁酸 Ο 3-(3-氣-4-異丙 氧基苯基)-5-(3-(0比咬-4-基)丙 基)-1，2,4-噚二 唑HC1鹽 358.27 (M+H)+ 3.11 (c) A.147 3-氯-4-¾丙基 曱氧基苄腈 (B) 1H-吲哚-4-曱酸 人矿w α 3-(3-氯-4-異丙 氧基苯基)-5-(1H-吲哚-4-基)-1，2,4^号二唑 354.17 (M+H)+ 2.69 (h) A.148 3-氣-4-¾丙基 曱氧基苄腈 (B) 4-胺磺醯基 苯甲酸 乂 Cl 4-(3·(3-氯-4-異 丙氧基苯基)-1，2,4-嘮二唑-5-基)笨磺醯胺 394.18 (M+H)+ 2.77 (c) A. 149 3-氯-4-環丙基 曱氧基苄腈 (B) 4-(經基甲 基)苯曱酸 人x/w Cl (4-(3-(3-氯-4-異 丙氧基苯基)-1，2,4-噚二唑-5-基)苯基)曱醇 345.16 (M+H)+ 2.80 (c) A.150 3 -氣-4-¾丙基 曱氧基苄腈 (B) 1，2,3,4-四氫 嗤淋-6-曱酸 人人&gt; 3-(3-氯-4-異丙 氧基苯基)-5-(1，2,3,4·四氫喹 琳-6-基)-1，2,4- 口号二峻 370.18 (M+H)+ 3.22 (c) 附註a :未提供酸或醯氯。該產物為製備4-[3-(3-氯-4-異丙 氧基-苯基）-[1，2,4]噚二唑-5-基]-吡啶之副產物。 附註b :化合物未在LCMS條件下離子化。1H NMR (Varia Inova 500 NMR 光譜儀（i499)，DMSO〇 δ 8.56-8.71 (m，1 127788.doc -120- 200840567 H)，8.44-8.54 (m，1 Η)，8·14-8·24 (m，1 Η)，8·06-8·11 (m，1 H)，7.84-7.93 (m，1 H)，7.34-7.47 (m，1 H)，4.67-5.00 (m，1 H)，1.36 (d，6 H) 〇 附註c :化合物未在LCMS條件下離子化。1h NMR (VariaExample number nitrile precursor acid or helium product name Rt/inin (method) m/z A. 129 4-butyl-benzonitrile 2-methyl-benzoquinone chloride 3-(4-butyl-phenyl) -5-o-indole phenyl-[1,2,4衿二σ sitting 3.55 (b) 293 (M+H)+ A.130 4-isopropyl-section guess 2-mercapto-benzhydryl chloride 3-(4-isopropyl-phenyl)-5-o-tolyl-[1,2,4]噚 two-seat 3.44 (b) 279 (M+H)+ A.131 benzonitrile is alkaloid Acid chloride 4-(3-phenyl-[l,2,4]oxadiazol-5-yl)·σ ratio bite 2.48 (f) 223 (M+H)+ A.132 3-chloro-benzonitrile醯 醯 N N,0\ c'x^n/&gt;^^n 4-[3-(3-Gas-phenyl)-[1,2,4]噚二°坐-5-基]- σ ratio. 2.75 (f) 258 (M+H)+ A. 133 4-hydroxy-benzonitrile isonicotinium chloride 4-(5-° ratio 1,4--4--[1,2,4]oxadiazole -3-yl)-phenol 1.95 (f) 240 (M+H)+ A.134 benzofuran-5-indolecarbonitrile 2-mercapto-benzoquinone 3-benzoquinone °f South-5-based -5-o-indolephenyl-[1,2,4]oxadiazole 3.83 (a) 277 (M+H)+ A.135 4-methoxy-trifluoromethyl-benzonitrile 2-methyl -benzoquinone chloride 3-(4-decyloxy-3-trifluoromethyl-phenyl)-5-o-indolephenyl-[1,2,4] 咢2 坐 sitting 3.31 (f) 335 (M+H)+ A.136 biphenyl-4-carbonitrile 2-mercapto-benzylidene chloride 3-biphenyl-4-yl-5-o-tolyl-[1,2,4]呤二Azole 3.38(f) 313 (M+H)+ 127788.doc 118- 200840567 Example number nitrile precursor acid or hydrazine chloride product name Rt/min (method) m/z A.137 3-chloro-4-isopropoxy Benzobenzonitrile (A) 2 piped dichloro-benzhydryl chloride (F) CI 乂^&gt; 5-, 3-(3-chloro-4-isopropoxy-phenyl)-5 stomach [2,4 -diqi-phenyl)-[1,2,4] s. oxadiazole 3.48 (f) 385 (M+H)+ A.138 3 - gas-4-3⁄4 propyl decyloxybenzonitrile (B) 4 -Amino-2-gasbenzoic acid CI Cl 3-Chloro (3-(3-chloro-4-isopropoxyphenyl)-1,2,4--diazol-5-yl)aniline 364.09 (M+H)+ 3.08(c) A.139 3-Actyl-4-3⁄4propyl decyloxybenzonitrile (B) 1-Mercapto-1H-pyrazole-5-decanoic acid η \ xx/w 3-(3-Actyl-4-isopropoxyphenyl)-5-(1-indolyl-m-« is more than -5,yl)-1,2,4-different TI sits at 319.25 ( M+H)+ 3.08(a) A.140 3 -Gas-4-3⁄4propylmethoxybenzonitrile (B) 1-isopropyl hydrazine D Dolin-4-pyruic acid Cl 3-(3- gas -4-Isopropoxyphenyl)-5-(1-isopropyl-indolyl-4-yl)-1,2,4- succinimide 396.22 (M+H)+ 2.40 (c) A.141 3 - murine-4-3⁄4 propyl decyloxybenzonitrile (B) 6- desert acid test 5-(6-inferior than bit-3-yl)-3 -(3 - gas-4- Isopropoxyphenyl)-1,2,4-oxadiazole 396.03 (M+H)+ 3.99 (a) A.142 3-chloro-4-3⁄4propylmethoxybenzonitrile (B) 4- 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl (1-cyanocyclopropyl)benzoate Cyclopropanil carbonitrile 380.43 (M+H)+ 3.19(c) A. 143 3-Chloro-halopropyl decyloxybenzonitrile (B) 6-bromonicotinium chloride/3-(3-chloro -4-Isopropoxyphenyl)-5-(6-gas 0-bit-3-yl)-1,2,4-oxadiazole 350.08 (M+H)+ 3.92 (a) A. 144 3 - gas-4-3⁄4 propyl decyloxybenzonitrile (B) 1-isopropyl porphyrin citrate human Cl 3- (3-Oxo-4-isopropoxyphenyl)-5-(1 ·Isopropylindole-4-yl)-1,2,4-吟 two-seat 398.20 (M+H)+ 3.56 (c) 127788.doc -119- 200840567 Example number nitrile precursor acid or helium product name Rt/min (method) m/z A.145 3-chloro-4-cyclopropyl decyloxybenzonitrile (B) 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid hr0, h&gt; Cl 3-(3-chloro-4.isopropoxyphenyl)-5-(1-(2,4-dichlorobenzene) Base) cyclopropyl)·1,2,4-, two-position 425,04 (M+H)+ 3.48 (c) A.146 3- gas-4-3⁄4 propyl decyloxybenzonitrile (B 4-(° ratio bit-4-yl)butyric acid strontium 3-(3- gas-4-isopropoxyphenyl)-5-(3-(0-bit-4-yl)propyl)- 1,2,4-oxadiazole HC1 salt 358.27 (M+H)+ 3.11 (c) A.147 3-chloro-4-3⁄4 propyl decyloxybenzonitrile (B) 1H-吲哚-4-曱Acid human ore w α 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4^diazole 354.17 (M+H) + 2.69 (h) A.148 3-Actyl-4-3⁄4 propyl decyloxybenzonitrile (B) 4-Aminesulfonylbenzoic acid 乂Cl 4-(3·(3-chloro-4-isopropyloxy) Phenyl)-1,2,4-oxadiazol-5-yl) oxasulfonamide 394.18 (M+H)+ 2.77 (c) A. 149 3-chloro-4-cyclopropyl decyloxybenzyl Nitrile (B) 4-( Methyl)benzoic acid human x/w Cl (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl) Sterol 345.16 (M+H)+ 2.80 (c) A.150 3 -Gas-4-3⁄4propyl decyloxybenzonitrile (B) 1,2,3,4-Tetrahydroindole-6-decanoic acid Everyone&gt; 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4·tetrahydroquinolin-6-yl)-1,2,4- s. Jun 370.18 (M+H)+ 3.22 (c) Note a: No acid or bismuth chloride is provided. This product was a by-product of the preparation of 4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-pyridine. Note b: The compound was not ionized under LCMS conditions. 1H NMR (Varia Inova 500 NMR spectrometer (i499), DMSO 〇 δ 8.56-8.71 (m, 1 127788.doc -120- 200840567 H), 8.44 - 8.54 (m, 1 Η), 8·14-8·24 ( m,1 Η),8·06-8·11 (m,1 H),7.84-7.93 (m,1 H),7.34-7.47 (m,1 H),4.67-5.00 (m,1 H), 1.36 (d,6 H) 〇Note c: The compound was not ionized under LCMS conditions. 1h NMR (Varia

Inova 500 NMR光譜儀（i499)，DMSO-A) δ 8·28-8·44 (m，2 H)，8.10-8.20 (m，2 H)，8.06-8.10 (m5 1 H)，7.99-8.04 (m，1 H)，7.30-7.51 (m，1 H)，4.71-4.97 (m，1 H)，1.37 (d，6 H)。 附註d :化合物未在LCMS條件下離子化。1h NMR (VariaInova 500 NMR spectrometer (i499), DMSO-A) δ 8·28-8·44 (m, 2 H), 8.10-8.20 (m, 2 H), 8.06-8.10 (m5 1 H), 7.99-8.04 ( m, 1 H), 7.30-7.51 (m, 1 H), 4.71-4.97 (m, 1 H), 1.37 (d, 6 H). Note d: The compound was not ionized under LCMS conditions. 1h NMR (Varia

Inova 500 NMR 光譜儀（i499)，DMSO-O δ 8.32-8.57 (m，1 H)，7.82-7.90 (m，1 H)，7.74-7.82 (m，1 H)，7·20-7·40 (m，1 H)，4.67-4.95 (m，1 H)，1·85-2·13 (m，2 H)，1.67-1.82 (m，2 H)，1.53-1.63 (m，1 H)，1·25-1·42 (m，9 H) 〇 附註e :化合物未在LCMS條件下離子化。1h NMR (400 MHz’ DMSO〇 δ 8.24 (s，2H)，8·08 (d，1H)，8·01 (dd，1H)， 7.40 (d，1H)，4_83 (sept，1H)，1.35 (d，6H)。 表Β·使用通用程序C、D或E、G及H進行之實例Inova 500 NMR spectrometer (i499), DMSO-O δ 8.32-8.57 (m, 1 H), 7.82-7.90 (m, 1 H), 7.74-7.82 (m, 1 H), 7·20-7·40 ( m,1 H), 4.67-4.95 (m,1 H),1·85-2·13 (m,2 H),1.67-1.82 (m,2 H),1.53-1.63 (m,1 H), 1·25-1·42 (m, 9 H) 〇Note e: The compound was not ionized under LCMS conditions. 1h NMR (400 MHz' DMSO 〇 δ 8.24 (s, 2H), 8.08 (d, 1H), 8.01 (dd, 1H), 7.40 (d, 1H), 4_83 (sept, 1H), 1.35 ( d, 6H). Table Β Example using general procedure C, D or E, G and H

nh2ohNh2oh

酸或醯氣Acid or helium

CNCN

通用 程序 C 通用 程序 D或EGeneral procedure C general procedure D or E

127788.doc • 121 - 200840567127788.doc • 121 - 200840567

實例 編號 腈前 驅物 酸或 醯氯 胺 結構 名稱 m/z Rt/min (方法） B.1 3-溴-4- 異丙氧 基苄腈 2'氯-4- 氰基苯 甲酸 吖丁啶-3-甲酸 0 Clv HO 1-(4-(3-(3-溴-4-異丙氧 基苯基)-1，2,4-哼二 唑-5-基)-3-氯苄基)吖丁 啶-3-曱酸’ 508.05 (M+H)+ 3.16 (a) B.2 3-氯-4- 異丙氧 基苄腈 3-氰基 苯甲酸 吖丁啶-3-甲酸 χχ/气。 OH 1-(3-(3-(3-氯-4-異丙氧 基苯基)-1,2,4』咢二 唑-5-基)节 基)吖丁啶-3-曱酸 428.19 (M+H)+ 1.41 (a) B.3 3·氯-4-異丙氧 基苄腈 2-氣-4- 氰基苯 曱酸 吖丁啶-3-曱酸 V~〇h 1-(3-氯-4-(3-(3-氣-4-異丙 氧基苯基)-1，2,4-噚二 唑-5-基)苄 基)吖丁啶-3-甲酸 462.16 (M+H)+ 2.05 (a) B.4 4-異丙氧 基-3-(三 氟曱基） 苄腈 4-氰基 苯甲酸 吖丁啶-3-曱酸 HO 1-(4-(3-(4-異 丙氧基_3-(二 氟曱基)苯 基)-U，4,号 二唑-5-基)苄 基)吖丁啶-3-甲酸 462.25 (M+H)+ 1.42 ⑻ B.5 3-乙氧 基-4-異 丙氧基 苄腈 4-氰基 苯甲酸 吖丁啶-3-甲酸 V-〇H 1-(4-(3-(3-乙 氧基-4-異丙 氧基苯基)-1，2,4-噚二 唑-5-基)苄 基)吖丁啶-3-曱酸 438.30 (M+H)+ 1.19 ⑻ B.6 3-氣-4- 異丙氧 基苄腈 4-氰基 苯曱酸 3-胺基 丙酸 /V OH 3-(4-(3-(3-氣-4-異丙氧 基苯基)-1，2,4』咢二 哇-5-基)节基 胺基)丙酸 416.50 (M+H)+ 1.82 (c) 127788.doc -122- 200840567 實例 編號 腈前 驅物 酸或 醯氯 胺 結構 名稱 m/z Rt/min (方法） B.7 4-嗎嚇^· 3-(三氟 甲基)苄 腈 4-氰基 苯甲酸 吖丁啶-3-甲酸 ^-OH 1-(4-(3-(4-^ 啉-3-(三氟甲 基)苯基)-1，2,4』号二 唑-5-基)苄 基)吖丁啶-3-甲酸 489.22 (M+H)+ 2.18 ⑻ B.8 4·異丙氧 基-3-曱 氧基苄 腈 4-氰基 苯曱酸 吖丁啶-3-曱酸 λ^Η&gt;λ V〇h 1-(4-(3-(4-異 丙氧基-3-甲 氧基苯基)-1，2,4-口咢二 唑-5-基)苄 基)吖丁啶-3-曱酸 424.37 (M+H)+ 1.41 ⑻ B.9 3-氯-4-異丙氧 基苄腈 ‘氰基-曱氧 基苯曱 酸 吖丁啶-3-曱酸 ο y~〇H 1-(4-(3-(3-氯-4-異丙氧 基苯基)-1，2,4-哼二 唑·5-基)-3-曱氧基苄基） 吖丁啶-3-曱 酸 458.19 (M+H)+ 2.05 ⑻ B.10 4-嗎琳-3-(三氟 甲基)苄 腈 2-氯-4- 氰基苯 曱酸 吖丁啶-3-甲酸 $ 0 1-(3-氯-4-(3-(4-嗎啦-3-(三氟曱基） 苯基)-U，4-喝二唑-5-基） 苄基)吖丁 咬-3-甲酸 523.21 (M+H)+ 2.23 (a) B.11 氯- 4-(四氫 呋喃-3-基氧基） 苄腈 4-氰基 苯曱酸 吖丁啶-3-曱酸 匕Ο ⑻小(4-(3-(3-氯-4-(四 氫呋喃-3-基 氧基)苯基)-1，2,4-吟二 唑·5-基)苄 基)吖丁啶 甲酸 454.19 (M-Η)- 1.98 (a) B.12 4-(四氫 呋喃-3-基氧基)-3-(三氟 甲基)苄 腈 4-氰基 苯甲酸 吖丁啶-3-甲酸 ό &gt;ΟΗ 1.(4-(3-(4- (四氫σ夫喃-3-基氧基)-3-(三氟甲基） 苯基)-1，2,4-p号二嗤-5-基) 苄基)吖丁 啶-3-曱酸 490.29 (M+H)+ 2.67 ⑻ -123 - 127788.doc 200840567 實例 編號 腈前 焉區物 酸或 醯氯 胺 結構 名稱 m/z Rt/min (方法） B.13 3-氣-4_ 異丙氧 基苄腈 4-氰基 苯甲酸 2-胺基 乙酸 F F 2-(4-(3-(3-氯-4-異丙氧 基苯基)-U，4-吟二 唑-5-基)苄基 胺基)乙酸 TFA salt 400.14 (M+H)+ 1.55 (c) B.14 3-氣-4- 異丙氧 基节腈 4-氰基 苯甲酸 甲酸 /^〇H 1-(4-(3-(3-氣-4-異丙氧 基苯基)-1，2,4-咩二 唑-5-基)苄 基)哌啶-4-甲 酸 456.61 (M+H)+ 1.95 (c) B.15 3-氯-4- 異丙氧 基苄腈 4-氰基 苯甲酸 1-胺基 環丙烷 甲酸 弋 HO ° 1-(4-(3-(3-氮-4-異丙氧 基苯基)-1,2,4_ 口咢二 峻-5-基)节基 胺基)環丙烷 曱酸 426.37 (M-Η)- 1.92 (c) B.16 3-氯-4- 異丙氧 基苄腈 2-氯-5- 氰基苯 曱酸 吖丁啶-3-甲酸 1-(4·氣-3-(3-(3-氯-4-異丙 氧基苯基)-1，2,4-吟二 唑-5-基)苄 基)吖丁啶-3-甲酸乙酸鹽 462.49 (M+H)+ 2.29 (b) B.17 苄腈 4-氰基 苯甲酸 吖丁啶-3-甲酸 HO 1-(4-(3-苯基-1，2,4-噚二 唑-5-基)苄 基)吖丁啶-3-曱酸 336.23 (M+H) 2.01 (b) B.18 3-氣斗 異丙氧 基苄腈 3-氰基 苯曱酸 2-胺基 乙酸 W'。 2-(3-(3-(3-氣-4-異丙氧 基苯基)-1，2,4-噚二 唑-5-基)苄基 胺基)乙酸 402.16 (M+H)+ 1.85 (f) 127788.doc 124- 200840567 實例 編號 腈前 驅物 酸或 酸氯 胺 結構 名稱 m/z Rt/min (方法） Β.19 4-異丙氧 基-3-(二 氟甲基） 苄腈 4-氰基 苯甲酸 吖丁啶-3-甲酸 HO 1-(4-(3-(4-異 丙氧基(三 氟甲基)苯 基)-l，2,4-噚 二唑-5-基)苄 基)吖丁啶-3-甲酸 462.25 (M+H)+ 1.42(f) Β.20 (S)-3-氯-4-(四氮 呋喃-3-基氧基） 苄腈 4-氰基 苯曱酸 吖丁啶-3_甲酸 6 (S&gt;l-(4-(3-(3-氯-4-(四 氫°夫喃-3-基 氧基)苯基)- 1，2,4-口 咢二 峻-5-基)苄 基)吖丁啶-3-曱酸 456.22 (M+H)+ 1.99 (a) Β.21 苄腈 4-氮基 苯甲酸 (1R，3S) -3-胺基 環戊烷 甲酸 V〇H (lR，3S)-3-(4-(3-苯基-1，2,4-口咢二 唑-5-基)苄基 胺基)環戊烷 曱酸 364.72 (M+H) 2.03 (b) Β.22 苄腈 4-氰》基 苯曱酸 (1R53R) -3-胺基 環戊烧 甲酸 q 々OH (lS，3R)_3-(4-(3-苯基-1，2,4』咢二 唑-5-基)苄基 胺基)環戊烷 甲酸 364.22 (M+H) 2.04 (b) 表C·使用通用程序C、D或E、I或J與K進行之實例Example number nitrile precursor acid or guanidine chloramine structure name m/z Rt/min (method) B.1 3-bromo-4-isopropoxybenzonitrile 2' chloro-4-cyanobenzoic acid azeidine- 3-formic acid 0 Clv HO 1-(4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-chlorobenzyl) Azetidine-3-decanoic acid ' 508.05 (M+H)+ 3.16 (a) B.2 3-chloro-4-isopropoxybenzonitrile 3-butyric acid azetidine-3-carboxylic acid hydrazine/ gas. OH 1-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4′′ oxadiazol-5-yl) benzyl) azetidin-3-decanoic acid 428.19 (M+H)+ 1.41 (a) B.3 3·Chloro-4-isopropoxybenzonitrile 2-Gas-4-Cyanobenzoic acid Azetidine-3-decanoic acid V~〇h 1- (3-Chloro-4-(3-(3-)-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid 462.16 (M+H)+ 2.05 (a) B.4 4-Isopropoxy-3-(trifluoromethyl)benzonitrile 4-cyanobenzoic acid azetidin-3-furic acid HO 1-(4- (3-(4-Isopropoxy-3-(difluoroindolyl)phenyl)-U,4,diazol-5-yl)benzyl)azetidine-3-carboxylic acid 462.25 (M+H ) + 1.42 (8) B.5 3-Ethoxy-4-isopropoxybenzonitrile 4-Acyanobenzoate azetidine-3-carboxylic acid V-〇H 1-(4-(3-(3-B Oxy-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-furic acid 438.30 (M+H)+ 1.19 (8) B.6 3-ox-4-isopropoxybenzonitrile 4-cyanobenzoic acid 3-aminopropionic acid/V OH 3-(4-(3-(3- gas-4-isopropoxyphenyl)) -1,2,4"咢二哇-5-yl) benzylamino)propionic acid 416.50 (M+H)+ 1.82 (c) 127788.doc -122- 200840567 Example number nitrile precursor acid or guanamine Knot Structure name m/z Rt/min (method) B.7 4-? scare ^· 3-(trifluoromethyl)benzonitrile 4-cyanobenzoic acid azetidine-3-carboxylic acid ^-OH 1-(4 -(3-(4-(Phosin-3-(trifluoromethyl)phenyl)-1,2,4′′)diazol-5-yl)benzyl)azetidine-3-carboxylic acid 489.22 (M+ H)+ 2.18 (8) B.8 4·Isopropoxy-3-decyloxybenzonitrile 4-cyanobenzoic acid azetiidine-3-decanoic acid λ^Η&gt;λ V〇h 1-(4- (3-(4-Isopropoxy-3-methoxyphenyl)-1,2,4-oxaoxadiazol-5-yl)benzyl)azetidine-3-furic acid 424.37 (M+ H)+ 1.41 (8) B.9 3-Chloro-4-isopropoxybenzonitrile 'cyano-decyloxybenzoate azetidine-3-decanoic acid ο y~〇H 1-(4-(3 -(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole·5-yl)-3-decyloxybenzyl)azetidine-3-furic acid 458.19 (M +H)+ 2.05 (8) B.10 4-Merlin-3-(trifluoromethyl)benzonitrile 2-chloro-4-cyanobenzoic acid azetiidine-3-carboxylic acid $ 0 1-(3-chloro 4-(3-(4-?-la-3-(trifluoromethyl)phenyl)-U,4-dioxazol-5-yl)benzyl)butyrate-3-carboxylic acid 523.21 (M+ H)+ 2.23 (a) B.11 chloro- 4-(tetrahydrofuran-3-yloxy)benzonitrile 4-cyanobenzoic acid azetiidine-3-decanoate 匕Ο (8) small (4-(3) -(3-chloro-4-(tetrahydrofuran-3-yloxy)phenyl)-1,2,4-oxadiazole·5-yl)benzyl)azetidinecarboxylic acid 454.19 (M-Η)- 1.98 (a) B.12 4-(Tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)benzonitrile 4-cyanobenzoic acid azetiidine-3-carboxylic acid hydrazine &gt;ΟΗ 1.(4- (3-(4-(tetrahydro-s-pentan-3-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-p-di-n-5-yl)benzyl) Azetidine-3-decanoic acid 490.29 (M+H)+ 2.67 (8) -123 - 127788.doc 200840567 Example number nitrile prozone or acid chloroamine structure name m/z Rt/min (method) B.13 3-gas-4_isopropoxybenzonitrile 4-cyanobenzoic acid 2-aminoacetic acid FF 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-U,4- Oxazol-5-yl)benzylamino)acetic acid TFA salt 400.14 (M+H)+ 1.55 (c) B.14 3-ox-4-isopropoxyacetonitrile 4-cyanobenzoic acid/ ^〇H 1-(4-(3-(3-Gas-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)piperidine-4-carboxylic acid 456.61 (M+H)+ 1.95 (c) B.15 3-Chloro-4-isopropoxybenzonitrile 4-cyanobenzoic acid 1-aminocyclopropanecarboxylic acid 弋HO ° 1-(4-(3-( 3-nitro-4-isopropoxyphenyl)-1,2,4_ 咢2 -5-5-yl) benzylamino)cyclopropane citric acid 426.37 (M-Η)- 1.92 (c) B.16 3-chloro-4-isopropoxybenzonitrile 2-chloro-5-cyanobenzene Butylbutyrate-3-carboxylic acid 1-(4·gas-3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl) Benzyl)azetidine-3-carboxylic acid acetate 462.49 (M+H)+ 2.29 (b) B.17 benzonitrile 4-cyanobenzoic acid azetidine-3-carboxylic acid HO 1-(4-(3- Phenyl-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-furic acid 336.23 (M+H) 2.01 (b) B.18 3-pipette isopropoxybenzyl Nitrile 3-cyanobenzoic acid 2-amino acetic acid W'. 2-(3-(3-(3-Ga-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzylamino)acetic acid 402.16 (M+H)+ 1.85 (f) 127788.doc 124- 200840567 Example number nitrile precursor acid or acid chloramine structure name m/z Rt/min (method) Β.19 4-isopropoxy-3-(difluoromethyl) benzyl Nitrile 4-cyanobenzoic acid azetidine-3-carboxylic acid HO 1-(4-(3-(4-isopropoxy)(trifluoromethyl)phenyl)-l,2,4-oxadiazole- 5-(yl)benzyl)azetidine-3-carboxylic acid 462.25 (M+H)+ 1.42(f) Β.20 (S)-3-chloro-4-(tetrazolfuran-3-yloxy)benzyl Nitrile 4-cyanobenzoate azetidine-3_carboxylic acid 6 (S&gt;1-(4-(3-(3-chloro-4-(tetrahydrofuran-3-yloxy)phenyl)) - 1,2,4-Butter 咢二峻-5-yl)benzyl)azetidin-3-indole 456.22 (M+H)+ 1.99 (a) Β.21 benzonitrile 4-nitrobenzoic acid ( 1R,3S)-3-Aminocyclopentanecarboxylic acid V〇H (lR,3S)-3-(4-(3-phenyl-1,2,4-oxaoxadiazol-5-yl)benzyl Amino)cyclopentane decanoic acid 364.72 (M+H) 2.03 (b) Β.22 benzonitrile 4-cyanobenzoic acid (1R53R)-3-aminocyclopentancarboxylic acid q 々OH (lS, 3R ) 3-(4-(3-phenyl-1,2,4′′ oxadiazol-5-yl)benzylamino)cyclopentyl Examples for the carboxylic acid 364.22 (M + H) 2.04 (b) using the general procedure C · Table C, D or E, I or J and K

νη2οηΗη2οη

通用程序 CGeneral procedure C

酸或醯氣 通用程序 D或ΕAcid or helium General procedure D or Ε

125- 127788.doc 200840567 實例 編後 腈前驅物 酸或 醯氯 第三 丁酯 結構 名稱 m/z Rt/min (方法） C.1 (Ζ)-Ν·-羥 基-1Η-吲 哚-4-曱脒 (carboximi damide) 3·氯-4- 異丙氧 基苯甲 酸 丙烯酸 第三丁 酯 Cl 0 3-(4-(5-(3-|ι-4-異丙氧基 苯基)-1，2,4-哼二唑-3-基)-1Η-吲哚· 1-基)丙酸 424.14 (M-H)· 2.41 (c) C.2 3-氣-4-異 丙氧基苄 腈 1H-吲哚_ 4-曱酸 2-氟丙 烯酸第 三丁酯 人 Cl 0 3-(4-(3-(3-氯-4-異丙氧基 口咢二口坐-5- 基)-1Η-吲哚- 1备2-氟丙 酸 444.14 (M+H)+ 2.20 (c) C.3 3-氯-4-異 丙氧基苄 腈 ΙΗ-吲哚-4-甲酸 4-溴丁 酸第三 丁酯 人 Cl 4-(4-(3-(3-氯-4-異丙氧基 苯基)-U，4-吟二吐-5-基)-1Η-吲哚-1-基)丁酸 440.21 (M+H)+ 2.95 ⑻ C.4 3-氯-4-異 丙氧基苄 腈 1H-吲哚-4-曱酸 曱基丙 烯酸第 三丁酯 人 Cl 〇 3仰-(3-氯-4-異丙氧基 苯基)-1，2,4- 口号二口坐-5-基)-1Η-吲哚-1-基)-2-甲基 丙酸 438.17 (M-H&gt; 2.47 (〇) C.5 4-嗎 (三氟曱 基)节腈 1H-吲哚-4-曱酸 丙稀酸 第三丁 酯 3-(4-(3-(4-嗎 琳-3-(三1曱 基)苯基)-1，2,4-噚二唑-5-基)-1Η-叫 | 哚-1-基)丙酸 487.56 (M+H)+ 2.79 (c) C.6 3-氯-4-異 丙氧基苄 腈 ΙΗ-吲哚-4-曱酸 溴乙酸 第三丁 酯 Λ, HO 2-(4-(3-(3-氯-4-異丙氧基 苯基)·1，2,4- 口咢二口坐-5-基)-1Η-吲哚-1-基)乙酸 TFA鹽 412.18 (M+H)+ 2.38 (c) C.7 3-氣-4-異 丙氧基苄 腈 1H-吲哚_ 4-曱酸 3-氯-2,2-二 曱基丙 酸乙酯 人导 C丨 〇 3-(4-(3-(3-氯_ 4-異丙氧基 苯基)-1,2,4- 口号二口坐-5-基)-1Η-吲哚-1 -基)-2,2-二 甲基丙酸 454.25 (M+H)+ 3.11 127788.doc -126- 200840567 實例 編後 腈前驅物 酸或 酿氣 第三 丁酯 結構 名稱 m/z Rt/min (方法） C.8 3-氯-4-異 丙氧基苄 腈 ΙΗ-吼口各 并[2,3-b]°比啶-4-曱酸 丙烯酸 第三丁 酯 人 Cl Ο 3-(4-(3-(3-氯-4-異丙氧基 苯基H，2,4-p号二峻-5-基)-1Η-σ比洛 并[2,3-b]吼 咬-1-基)丙酸 427.17 (M+H)+ 2.84 (c) 表D.使用通用程序C、D或E及I之實例125-127788.doc 200840567 Example post-nitrile precursor acid or hydrazine chloride tert-butyl ester structure name m/z Rt/min (method) C.1 (Ζ)-Ν·-hydroxy-1Η-吲哚-4- Carboximi damide 3·chloro-4-isopropoxybenzoic acid tert-butyl acrylate Cl 0 3-(4-(5-(3-|ι-4-isopropoxyphenyl)-1 , 2,4-oxadiazol-3-yl)-1Η-吲哚·1-yl)propionic acid 424.14 (MH)· 2.41 (c) C.2 3-ox-4-isopropoxybenzonitrile 1H -吲哚_ 4-decanoic acid 2-fluoroacrylic acid tert-butyl ester human Cl 0 3-(4-(3-(3-chloro-4-isopropoxy oxime) 2 坐-5-yl)-1Η -吲哚-1 Preparation of 2-fluoropropionic acid 444.14 (M+H)+ 2.20 (c) C.3 3-Chloro-4-isopropoxybenzonitrile ΙΗ-吲哚-4-carboxylic acid 4-bromobutyric acid Third butyl ester human Cl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-U,4-indolyl-5-yl)-1Η-indol-1-yl ) Butyric acid 440.21 (M+H)+ 2.95 (8) C.4 3-Chloro-4-isopropoxybenzonitrile 1H-indole-4-decanoic acid decyl acrylate third butyl ester Cl 〇 3 - - ( 3-chloro-4-isopropoxyphenyl)-1,2,4- succinyl 2-sodium-5-yl)-1Η-indol-1-yl)-2-methylpropionic acid 438.17 (M- H&gt; 2.47 (〇) C.5 4-? (Trifluoromethyl) Nitrile 1H-indole-4-decanoic acid tert-butyl 3-butyl 3-(4-(3-(4-morphin-3-(tris-yl)phenyl)-1,2,4-indole Diazol-5-yl)-1Η-called | 哚-1-yl)propionic acid 487.56 (M+H)+ 2.79 (c) C.6 3-chloro-4-isopropoxybenzonitrile ΙΗ-吲哚-4-decanoic acid bromoacetic acid tert-butyl ester oxime, HO 2-(4-(3-(3-chloro-4-isopropoxyphenyl)·1,2,4-mouth 咢 two sitting -5 -yl)-1Η-indol-1-yl)acetic acid TFA salt 412.18 (M+H)+ 2.38 (c) C.7 3-ox-4-isopropoxybenzonitrile 1H-吲哚_ 4-曱Acid 3-Chloro-2,2-dimercaptopropionate human C丨〇3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4- Slogan two sitting on -5-yl)-1Η-吲哚-1 -yl)-2,2-dimethylpropionic acid 454.25 (M+H)+ 3.11 127788.doc -126- 200840567 Example post-nitrile precursor Acid or brewing gas, third butyl ester structure name m/z Rt/min (method) C.8 3-chloro-4-isopropoxybenzonitrile 吼-吼口[2,3-b]° pyridine -4-decanoic acid, tert-butyl acrylate, human Cl Ο 3-(4-(3-(3-chloro-4-isopropoxyphenyl H, 2,4-p-di-n-5-yl)- 1Η-σBiluo[2,3-b]bite-1-yl)propionic acid 427.17 (M+H)+ 2.84 (c) Table D. Using general procedure C, D or E The example I

實例 編號 腈前驅物 酸或 酸氯 胺 結構. 名稱 m/z Rt/min (方法） D.1 4-嗎啉-3-(三氟曱 基抒腈 4-氟 苯甲 醯氯 (1R53S) -3-胺基 環戊烷 曱酸 (1R，3S&gt;3-(4-(3-(4-嗎 啉-3-(三氟 甲基)苯 基)-1，2,4· 口咢二口坐-5-基)苯基胺 基)環戊烷 曱酸 503.21 (M-H)+ 3.31 (a) D.2 3-氣-4-異 丙氧基苄 腈 4-溴 苯曱 醯氯 (1R，3R) -3-胺基 環戊烷 曱酸 〇γ〇Η Ν-〇χ /=- Ο (lS，3R)-3-(4-(3-(3-氯_4_異丙 氧基苯基)-1，2,4-口号二 唑-5-基)苯 基胺基)環 戊烷甲酸 D.3 苄腈 4-氟 苯甲 酿氯 (1R，3S) -3-胺基 環戊烷 甲酸 〇VOH Ν-0 1 Η (1R53S&gt;3-(4-(3-苯基· 1,2,和号二 唑-5-基)苯 基胺基)環 戊烧甲酸 350.16 (M-H)+ 2.99 (a) 127788.doc -127- 200840567 表Ε·使用通用程序Μ、N、D及Ο進行之實例 〇丫〇、R 〇 丫〇、R ΟγΟΗ R2- rv 通用程序 通用程序 Y：c OH Μ Χκ N % 〇&gt; rM：Example number nitrile precursor acid or acid chloramine structure. Name m/z Rt/min (method) D.1 4-morpholine-3-(trifluoromethyl phthalonitrile 4-fluorobenzhydryl chloride (1R53S) - 3-aminocyclopentane decanoic acid (1R, 3S&gt; 3-(4-(3-(4-morpholin-3-(trifluoromethyl)phenyl)-1,2,4· 咢 咢Sodium-5-yl)phenylamino)cyclopentane decanoic acid 503.21 (MH)+ 3.31 (a) D.2 3-ox-4-isopropoxybenzonitrile 4-bromophenylhydrazine chloride (1R, 3R)-3-Aminocyclopentane decanoic acid 〇γ〇Η Ν-〇χ /=- Ο (lS,3R)-3-(4-(3-(3-chloro-4-isopropoxybenzene) Base)-1,2,4-spo-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid D.3 benzonitrile 4-fluorobenzyl chloride chlorine (1R,3S)-3-aminocyclopentane Bismuth alkanoate VOH Ν-0 1 Η (1R53S&gt; 3-(4-(3-phenyl·1,2, and oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid 350.16 (MH)+ 2.99 (a) 127788.doc -127- 200840567 Table Ε Example using general procedures Μ, N, D and 〇丫〇, R 〇丫〇, R Ο ΟΗ ΟΗ R2- rv General procedure General procedure Y: c OH Μ Χκ N % 〇&gt; rM:

羥基甲脒 3C&gt;&lt;Hydroxymethine 3C&gt;&lt;

通用程序 D 實例 編號 腈前 驅物 酚 醇 結構 名稱 m/z Rt/min (方法） E.l 3'氯-4- 異丙氧 基苄腈 4-羥基 苯甲酸 苄酯 (S)-(2,2-di甲基-1，3-二氧 雜環戊-4_基)甲 醇 C1 (R)-3-(4-(3-(3-|i-4-異丙氧基苯基)-1，2,4-噚二唑-5-基） 苯氧基)丙烧-1，2-二醇 405.25 (M+H)+ 2.72 (b) E.2 3-氯-4-異丙氧 基苄腈 4-羥基 苯曱酸 苄酯 (2,2-di 曱 基-1，3-二 氧雜環 己-5-基） 曱醇 HO 人 Cl 2-((4-(3-(3-氯-4-異 丙氧基苯基)-1，2,4-呤二唑-5-基)苯氧 基)曱基)丙烷-1，3-二醇 419.23 (M+H)+ 3.08(g) E.3 3-氯-4- 異丙氧 基苄腈 2-氯-4- 羥基苯 甲酸甲 酯 (S)-(2,2-di甲基-1，3-二氧 雜環戊-4-基)甲 醇 Cl、 N-0 Cl OH ⑻各(3-氣斗(3-(3-氣-4-異丙氧基 苯基)-1，2,4’亏二 唑-5-基)苯氧基)丙 烷-1，2-二醇 439.16 (M+H)+ 2.83 (a) 其他實例之製備 實例編號1 : 3-氯-4-異丙氧基-苯甲酸之製備General procedure D Example number nitrile precursor phenolic structure name m/z Rt/min (method) El 3' chloro-4-isopropoxybenzonitrile benzyl 4-hydroxybenzoate (S)-(2,2- Dimethyl-1,3-dioxol-4-yl)methanol C1 (R)-3-(4-(3-(3-|i-4-isopropoxyphenyl)-1, 2,4-oxadiazol-5-yl)phenoxy)propanone-1,2-diol 405.25 (M+H)+ 2.72 (b) E.2 3-chloro-4-isopropoxybenzyl Nitrile 4-hydroxybenzoic acid benzyl ester (2,2-didecyl-1,3-dioxan-5-yl) decyl alcohol HO human Cl 2-((4-(3-(3-chloro) -4-Isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)indolyl-propane-1,3-diol 419.23 (M+H)+ 3.08 (g E.3 3-Chloro-4-isopropoxybenzonitrile 2-chloro-4-hydroxybenzoic acid methyl ester (S)-(2,2-dimethyl-1,3-dioxolane- 4-yl)methanol Cl, N-0 Cl OH (8) each (3-pipe (3-(3- gas-4-isopropoxyphenyl)-1,2,4' bisoxazol-5-yl) Phenoxy)propane-1,2-diol 439.16 (M+H)+ 2.83 (a) Preparation of other examples Example No. 1: Preparation of 3-chloro-4-isopropoxy-benzoic acid

於圓底瓶中添加三苯基膦（62克，0.263莫耳）、3-氯-4-羥 基-苯甲酸甲酯（10克，0.0535莫耳）及無水THF(500毫升）。 127788.doc -128- 200840567 使混合物在氮氣中簡單攪拌，接著添加dbAD(19.75克， 0·0858莫耳）。使混合物攪拌數分鐘，接著添加無水異丙醇 (5.125毫升，〇·〇67莫耳）。反應混合物在室溫下及氮氣中 攪拌約3小時後，添加DBAD(19.75克，〇〇858莫耳）及無水 異丙醇（5·125毫升，0.067莫耳），且使混合物在室溫下攪 拌隔夜。減壓移除溶劑。使殘留物溶於最小量之乙酸乙 醋。添加庚烧且過濾移除沉澱物。將濾液加於甲醇中。加 水直到渾濁為止。過濾沉澱物。再重複甲醇/水沉澱程序 兩次。將濾液置於THF(200毫升）及5 M Na〇H(2〇〇毫升） 中。使混合物在室溫下攪拌隔夜。減壓移除有機溶劑。水 層以乙酸乙酯萃取三次。以2 M HC1使水層進一步酸化至 pH 1 -2。接著以乙酸乙酯萃取渾濁之懸浮液三次。合併有 機層，以硫酸鎂脫水且濃縮至乾，獲得3-氣_4_異丙氧基_ 苯甲酸（8.4克，71.4%)之白色固體。 LC/MS (表 1，方法b) Rt=2.42 min，m/z (M-H)· 213;巾 NMR (400 MHz，DMSO〇 δ12·95 (s，1H)，7·87 (m，2H)， 7.25 (d，1H)，4.79 (m，1H)，1.32 (d，6H)。 實例編號2 : 4-(3·(3·氣·4_異丙氧基苯基噚二唑 基）苄腈Triphenylphosphine (62 g, 0.263 mol), 3-chloro-4-hydroxy-benzoic acid methyl ester (10 g, 0.0535 mol) and anhydrous THF (500 mL) were added to a round bottom flask. 127788.doc -128- 200840567 The mixture was briefly stirred under nitrogen, followed by the addition of dbAD (19.75 g, 0·0858 mol). The mixture was stirred for a few minutes, followed by the addition of anhydrous isopropanol (5.125 mL, 〇·〇 67 Mo). After the reaction mixture was stirred at room temperature under nitrogen for about 3 hours, DBAD (19.75 g, 〇〇858 mol) and anhydrous isopropanol (5.125 ml, 0.067 mol) were added, and the mixture was allowed to stand at room temperature. Stir overnight. The solvent was removed under reduced pressure. The residue is dissolved in a minimum amount of ethyl acetate. The heptane was added and the precipitate was removed by filtration. The filtrate was added to methanol. Add water until it is cloudy. The precipitate was filtered. The methanol/water precipitation procedure was repeated twice more. The filtrate was taken up in THF (200 mL) and 5 M NaH (2 mL). The mixture was allowed to stir at room temperature overnight. The organic solvent was removed under reduced pressure. The aqueous layer was extracted three times with ethyl acetate. The aqueous layer was further acidified to pH 1-2 with 2 M HCl. The cloudy suspension was then extracted three times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness to afford white crystals of 3-- 4-isopropoxy-benzoic acid (8.4 g, 71.4%). LC/MS (Table 1, Method b) Rt=2.42 min, m/z (MH)· 213; NMR (400 MHz, DMSO 〇 δ12·95 (s, 1H), 7·87 (m, 2H), 7.25 (d,1H), 4.79 (m,1H), 1.32 (d,6H). Example No. 2: 4-(3·(3·Ga·4_isopropoxyphenyloxadiazolyl)benzonitrile

在氮氣中使3-氣-N-羥基-4-異丙氧基苯甲脒（1〇克，43.7 宅莫耳）溶於DMF(219毫升）中。使混合物在約no°c下加熱 127788.doc -129- 200840567 、、句1〇刀鐘。在約20分鐘内滴加溶於DMF(3〇毫升）中之心气 基笨甲醯氣（7.24克，43·7毫莫耳）溶液且使反應在約11〇^ 下加熱約4 h，直到LCMS顯示反應完全為止。使反應於冰 浴中冷卻且倒入快速攪拌之水（1〇〇〇毫升）中。真空過濾收 集所知白色沉澱物且以水洗滌。使沉澱物溶於二氯曱烷中 且以1 N HC1洗滌接著以鹽水洗滌。以硫酸鈉使二氯甲烷 脫水，經過濾且瘵發。於殘留物中添加庚烷及dcm，且將 混合物加熱直到DCM沸騰去除掉為止，隨後使混合物冷 部。固體不溶於熱庚烷中。真空過濾收集所得固體且以庚 烷洗滌，獲得褐色固體之4_(3_(3_氯_4•異丙氧基苯基 1，2,4-嘮二唑-5-基）苄腈（12·568克，37〇毫莫耳，產率 85%)。LCMS(表 1，方法 a) Rt=4 58 min ;⑽油·· 34〇 2〇 (M+H)+ 〇 實例編號3 · 4-(3-(3_氣_4_異丙氧基苯基噚二唑_s_ 基）苯甲醛3-Gas-N-hydroxy-4-isopropoxybenzidine (1 g, 43.7 house moles) was dissolved in DMF (219 mL). The mixture is heated at about no ° c 127788.doc -129- 200840567, sentence 1 knives. A solution of heart-based arachidyl (7.24 g, 43. 7 mmol) dissolved in DMF (3 mL) was added dropwise over about 20 minutes and the reaction was heated at about 11 Torr for about 4 h until LCMS showed the reaction was complete. The reaction was cooled in an ice bath and poured into rapidly stirred water (1 mL). The known white precipitate was collected by vacuum filtration and washed with water. The precipitate was dissolved in dichloromethane and washed with 1 N EtOAc then brine. The methylene chloride was dehydrated with sodium sulfate, filtered and spun. Heptane and dcm were added to the residue, and the mixture was heated until DCM was boiled off, and then the mixture was allowed to cool. The solid is insoluble in hot heptane. The resulting solid was collected by vacuum <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0> 568 g, 37 〇 mmol, yield 85%) LCMS (Table 1, Method a) Rt = 4 58 min; (10) Oil · · 34 〇 2 〇 (M+H) + 〇 Example No. 3 · 4- (3-(3_gas_4_isopropoxyphenyloxadiazole_s_yl)benzaldehyde

在氮氣中使4-(3-(3-氯-4-異丙氧基苯基呤二唑_5_ 基）苄腈（10克，29.4毫莫耳）溶於二氯甲烷（535毫升）中。使 反應於乾冰/乙腈浴中冷卻至測量内溫約_4Ό。〇。滴加 Dibal-H溶液（58.9毫升，58·9毫莫耳）且使反應攪拌約3〇分 鐘，並以甲醇終止反應。攪拌混合物直到消泡為止。接著 使混合物升溫至室溫且與10% R〇cheUe，s鹽溶液快速攪 127788.doc -130· 200840567 拌。分離之層以DCM(3xl00毫升）萃取三次。合併之萃取 液與約100毫升之1 N HC1快速攪拌，且溶液由橘色變為無 色。TLC顯不混合物已經乾淨至以有些基準線材料測恰僅 有一點。使層分離且以DCM(2xl00毫升）萃取水層。合併 之有機萃取液以鹽水洗滌，以硫酸納脫水，經過濾且蒸發 至乾，獲得灰白色固體。使固體與庚烧擾拌且以移液管小 心移除溶劑。固體經真空乾燥，獲得白色固體之4-(3-(3-氣-4·異丙氧基本基）-1,2,4-17亏二°坐-5-基）苯曱酸（9·15克， 26.7¾ 莫耳 ’ 91%)。LCMS(表 1 ’ 方法 a) Rf=4 · 5 9 min.; MS w/z: 343.26, 345·18 (M+H)+。 實例編號4 : l_(4-(3-(3-氣_4_異丙氧基苯基）4,2,4-嘮二唑_ 5-基）苄基）吖丁啶-3·甲酸之製備4-(3-(3-Chloro-4-isopropoxyphenyloxadiazole-5-yl)benzonitrile (10 g, 29.4 mmol) was dissolved in dichloromethane (535 mL). The reaction was allowed to cool in a dry ice/acetonitrile bath until the internal temperature was measured to be about _4 Ό. Dibal-H solution (58.9 ml, 58·9 mmol) was added dropwise and the reaction was stirred for about 3 minutes and terminated with methanol. The mixture was stirred until defoaming. The mixture was then warmed to room temperature and stirred with 10% R 〇che Ue, s salt solution 127 788. doc - 130 · 200840567. The separated layer was extracted three times with DCM (3×10 mL). The combined extracts were rapidly stirred with about 100 mL of 1 N HCl and the solution changed from orange to colorless. The TLC mixture was cleaned to a point with some baseline material. The layers were separated and DCM (2×100) The aqueous extracts were extracted with EtOAc. EtOAc (EtOAc)EtOAc. Drying in vacuo to give 4-(3-(3- gas-4.isopropoxy) 2, 4-17 minus 2 ° sitting -5-yl) benzoic acid (9·15 g, 26.73⁄4 Moer '91%). LCMS (Table 1 'Method a) Rf = 4 · 5 9 min.; MS w/z: 343.26, 345·18 (M+H)+. Example No. 4: l_(4-(3-(3-Gas_4_isopropoxyphenyl)4,2,4-oxadiazole Preparation of _ 5-yl)benzyl)azetidine-3·formic acid

使°丫丁°疋-3 -甲酸（3.72克’ 36.8愛莫耳）（Synchem)溶於乙 酸（16.03毫升，280毫莫耳）及甲醇（2毫升）中。將其添加於 含4-(3-(3-氯-4-異丙氧基苯基）_1，2,4_号二嗤-5-基）苯甲酸 (12克，35.0毫莫耳）之MeOH(600毫升）授拌懸浮液中。使 反應授拌約1 8 h。添加氣基则氫化鈉（$ · $ 〇克，8 8毫莫 耳），且使反應攪拌約4 h。反應以冰浴冷卻且真空過濾收 集沉殿物，並經冰冷之甲醇洗滌，接著以乙醚洗務。TLc 顯示仍存在雜質。使固體溶於1:1之 127788.doc -131 - 200840567 CHCl3/MeOH/NH4〇H)中，且NH4OH稍超過量添加。在矽 膠上層析，以 1:1 之 EtOAc/(6:3:l CHCl3/MeOH/NH4OH)之 混合物增加至全部為（6:3:1 CHCl3/MeOH/NH4OH)之混合物 使產物溶離。使溶離份蒸發至乾，獲得無色薄膜/油。添 加曱醇且使混合物形成旋渦，但此會造成過濾時之回收 低。使混合物溶於曱醇中且蒸發濾液至乾。使殘留物再懸 浮於最小量之甲醇中，加水且過濾混合物，以水洗滌再以 乙醚洗滌。使殘留物在周圍溫度下真空乾燥，接著在約6〇 °(：下真空移除微量之甲醇，獲得白色固體之^(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-噚二唑-5-基）苄基）吖丁啶-3 -甲酸 (8.3克，19.40毫莫耳，產率55.4%) : LCMS(表1，方法a) R,=2.94 min.; MS m/z: 428.31? 430.27 (M+H)+; mp 194.8-195.9 °C; lR NMR (400 MHz, DMSO) δ ppm 8.12 (d, J=8.34 Hz，2H)，8.06 (d，/=2.13 Hz，1H)，8.00 (dd，/=8.67, 2·15 Hz，1H)，7·54 (d，《7=8.36 Hz，2H)，7·39 (d，《7=9.06 Hz， 1H)，4.88-4.77 (m，1H)，3·67 (s，2H)，3·48-3·38 (m，2H)， 3·29-3·19 (m，3H)，1·35 (d，/=6.02 Hz，6H)。 實例編號5: 3-(3-氣-4-異丙氧基苯基）-5-(4 -氣苯基）-1，2,4-噚二唑之製備The solution was dissolved in acetic acid (16.03 ml, 280 mmol) and methanol (2 mL). It was added to 4-(3-(3-chloro-4-isopropoxyphenyl)_1,2,4-dioxa-5-yl)benzoic acid (12 g, 35.0 mmol). MeOH (600 mL) was added to the suspension. The reaction was allowed to mix for about 18 h. Add sodium hydride ($·$ gram, 8 8 mmol) and stir the reaction for about 4 h. The reaction was cooled in an ice-bath and vacuum filtered to dryness and washed with ice cold methanol and then ether. TLc shows that impurities are still present. The solid was dissolved in 1:1 127788.doc -131 - 200840567 CHCl3 / MeOH / NH4 〇H), and NH4OH was added in a little excess. Chromatography on ruthenium, a mixture of 1:1 EtOAc / (6:3:1 CHCl3 / MeOH / NH4OH) was added to a mixture of all (6:3:1 CHCl3 / MeOH / NH4OH) to dissolve the product. The dissolved fraction was evaporated to dryness to give a colorless film/oil. The sterol is added and the mixture is vortexed, but this results in low recovery during filtration. The mixture was dissolved in methanol and the filtrate was evaporated to dryness. The residue was resuspended in a minimum amount of methanol, water was added and the mixture was filtered, washed with water and washed with diethyl ether. The residue was dried under vacuum at ambient temperature, followed by removal of a trace of methanol in vacuo to afford a white solid ((4-(3-(3-)). -1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid (8.3 g, 19.40 mmol, yield 55.4%): LCMS (Table 1, Method a) R , = 2.94 min.; MS m/z: 428.31? 430.27 (M+H)+; mp 194.8-195.9 °C; lR NMR (400 MHz, DMSO) δ ppm 8.12 (d, J = 8.34 Hz, 2H), 8.06 (d, /=2.13 Hz, 1H), 8.00 (dd, /=8.67, 2·15 Hz, 1H), 7·54 (d, “7=8.36 Hz, 2H), 7·39 (d, “ 7=9.06 Hz, 1H), 4.88-4.77 (m,1H),3·67 (s,2H),3·48-3·38 (m,2H), 3·29-3·19 (m,3H ), 1·35 (d, /=6.02 Hz, 6H). Example No. 5: 3-(3-Gas-4-isopropoxyphenyl)-5-(4-phenylphenyl)-1,2 Preparation of 4-oxadiazole

將（Z)-3-氯-Ν’-羥基-4-異丙氧基苯甲脒（2.0克，8·75毫莫 耳）、4-氟苯曱醯氣（2.1克，13.12毫莫耳）及吼啶（12毫升） 加於20毫升之裝置有攪拌棒之微波瓶中。將該瓶密封且配 127788.doc -132- 200840567 合冷卻使反應加熱至2 0 0 °C歷時2 5分鐘。使用正相層析將 反應混合物純化，獲得淺棕色固體。經LCMS分析顯示為 3-(3 -氣-4-異丙氧基苯基）-5-(4-氟苯基）-1，2，4 -崎二τι坐、2_ 氯-4-(5-(4-鼠苯基）-1，2，4-p号二峻-3-基）苯盼及4-氣苯甲酸 之35 :30:21混合物。使用正相層析將混合物第二次純化， 獲得5種溶離份。合併溶離份1、2及3且蒸發至乾獲得白色 固體之3-(3-氯-4-異丙氧基苯基）-5-(4-氟苯基）-i，2,4-吟二 唑（420毫克，14%) 10023683-145-P1。LCMS(表 1，方法a) Rt=2.85 min，m/z 333.10 (M-H)+ 〇 實例編號6 : 3-氣-4-(3-(3-氣-4·異丙氧基苯基）^2,4-噚二 唑_5_基）苄腈之製備(Z)-3-Chloro-indole'-hydroxy-4-isopropoxybenzamide (2.0 g, 8.75 mmol), 4-fluorobenzoquinone (2.1 g, 13.12 mmol) And acridine (12 ml) was added to a 20 ml microwave bottle with a stir bar. The bottle was sealed and cooled with 127788.doc -132-200840567 and the reaction was heated to 200 °C for 25 minutes. The reaction mixture was purified using normal phase chromatography to give a pale brown solid. Analysis by LCMS showed 3-(3- gas-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-sodium sulphonium, 2 chloro-4-(5 a mixture of -(4-murophenyl)-1,2,4-p-di-tert--3-yl)benz and 4-oxobenzoic acid 35:30:21. The mixture was purified a second time using normal phase chromatography to obtain 5 kinds of dissolved fractions. The combined fractions 1, 2 and 3 were combined and evaporated to dryness to give 3-(3-chloro-4-isopropoxyphenyl)-5-(4-fluorophenyl)-i,2,4-indole as a white solid. Diazole (420 mg, 14%) 10023683-145-P1. LCMS (Table 1, Method a) Rt = 2.85 min, m/z 333.10 (MH) + 〇 Example No. 6: 3- -4-(3-(3- s. Preparation of 2,4-oxadiazole-5-yl)benzonitrile

nh2 n，ohNh2 n,oh

於裝置有攪拌棒之250毫升RBF中注入2-氣-4-氰基苯曱 酸（3.0克’ 16.52毫莫耳）、無水DCM(80毫升）及DMF(0.0642-Gas-4-cyanobenzoic acid (3.0 g ' 16.52 mmol), anhydrous DCM (80 mL) and DMF (0.064) were injected into 250 ml of RBF equipped with a stir bar.

耄升，〇·826毫莫耳）。接著緩慢添加草醯氣（8 26毫升， 16.52¾莫耳）（2 Μ於DCM之溶液）且使混合物在周圍溫度下 及氮氣中攪拌。添加草醯氣後，開始釋出氣體且懸浮固體 開始溶解。約2-3小時後，反應變成透明。真空濃縮混合 物。使所得粗製混合物溶於吡啶（5〇毫升）中。於其中添加 (Ζ)-3-氯-ν’-羥基-4-異丙氧基苯曱脒（1258克，55〇毫莫 耳）。使混合物在氮氣中加熱至約l〇〇t：歷時約16小時。使 2得混合物冷卻至周圍溫度。減壓移除吡啶，且使所得物 質研散於DCM及MeOH混合物（約1:1)中。使所得沉殿物在 127788.doc -133· 200840567 周圍溫度下靜置數分鐘，接著以過濾收集。以1 ·丨之 DCM/MeOH混合物洗滌，且接著直接以Me〇H洗滌並於真 空烘箱中乾燥約48小時，獲得褐色固體之夂氣_4_(3_(3_氯_ 4·異丙氧基苯基）-1，2,4-吟二唑·5_基）苄腈（1529克，4〇9毫 莫耳）。巾 NMR (400 ΜΗζ，Ζ)Μ5Ό) δ ppm 8.39 (d，/吐53 Hz，1H)，8·35 (d，&gt;8·15 Hz，1H)，8·09 (dd，/=8·14, 1·53 Hz，1H)，8·05 (d，/=2·11 Hz，1H)，8.00 (dd，/=8.63，2·12Soaring, 〇 826 millimoles). Then, grasshopper gas (8 26 ml, 16.523⁄4 mol) (2 Torr in DCM) was added slowly and the mixture was stirred at ambient temperature under nitrogen. After the addition of grass helium, gas evolution begins and the suspended solids begin to dissolve. After about 2-3 hours, the reaction became transparent. The mixture was concentrated in vacuo. The resulting crude mixture was dissolved in pyridine (5 mL). (Ζ)-3-Chloro-ν'-hydroxy-4-isopropoxyphenylhydrazine (1258 g, 55 〇 millimolar) was added thereto. The mixture was heated to about 1 Torr in nitrogen for about 16 hours. The mixture was allowed to cool to ambient temperature. The pyridine was removed under reduced pressure, and the resultant material was crystallized from a mixture of DCM and MeOH (about 1:1). The resulting sinking matter was allowed to stand at ambient temperature of 127788.doc - 133 · 200840567 for several minutes, and then collected by filtration. It was washed with a DCM/MeOH mixture of hydrazine, and then directly washed with Me 〇H and dried in a vacuum oven for about 48 hours to obtain a helium gas of a brown solid _4_(3_(3_chloro_4·isopropoxy) Phenyl)-1,2,4-oxadiazole·5-yl)benzonitrile (1529 g, 4 〇 9 mmol). NMR (400 ΜΗζ, Ζ) Μ 5 Ό) δ ppm 8.39 (d, / spit 53 Hz, 1H), 8.35 (d, &gt; 8·15 Hz, 1H), 8·09 (dd, /=8· 14, 1·53 Hz, 1H), 8·05 (d, /=2·11 Hz, 1H), 8.00 (dd, /=8.63, 2.12

Hz，1H)，7.39 (d，&gt;8·82 Hz，1H)，4.82 (sept，〇4 Hz， 1H)，1.35 (d，J=6.01 Hz，6H)。 實例編號7 : 2-(4-(3-(3-氣_4-異丙氧基苯基）_1，2,4j号二唑-5-基）苯基）丙烧-2-胺之製備Hz, 1H), 7.39 (d, &gt; 8·82 Hz, 1H), 4.82 (sept, 〇4 Hz, 1H), 1.35 (d, J = 6.01 Hz, 6H). Example No. 7: Preparation of 2-(4-(3-(3-Gas-4-isopropoxyphenyl)_1,2,4j-diazol-5-yl)phenyl)propan-2-amine

• 浮液經超音坡數分鐘，且接著在室溫下攪拌約90分鐘• The float passes through the ultrasonic slope for a few minutes and then stirs at room temperature for about 90 minutes

在氮氣中將無水氣化鈽（111)(557克，22·6〇毫莫耳）及無 水四氫呋喃（20毫升）添加於無水2_頸圓底瓶中。使所得懸 π主 卜視秤約y ϋ分鐘。接 緩慢添加甲基鋰（14· 1 3毫 升，22.60¾莫耳約6〇分鐘且升溫至約後，使反應冷 卻至-5(TC，且滴加含4_(3-(3_氣_4_異丙氧基苯基，‘吟 二唑-5-基）苄腈（2.4克，7_〇6毫莫耳）之8毫升無水τΗρ，使 反應溫度維持在約_5(TC。使反應維持在巧〇χ：歷時丨小時， 接著使之升溫至周圍溫度隔夜。次日使反應冷卻至_5〇 °c，且藉添加21毫升之35% ΝΗ4〇ί^$止反應。使終止之反 127788.doc -134- 200840567 應升溫至室溫歷時兩天。混合物經Celite®過濾且以 DCM(4x60毫升）洗滌。收集濾液且接著以水洗滌，並以 MgSCU脫水。減壓移除溶劑且使粗製產物經Rp_ HPLC(A=50 mM乙酸銨，乙腈；30-70% B歷時30·0分鐘 (流速 21.0¾ 升/分鐘），21.2x250^；求 Thermo Hyper prep C18管柱，8 μπ^子）純化，獲得2-(4-(3-(3-氯-4-異丙氧基 苯基）-1，2,4-0号二峻-5-基）苯基）丙烧-2-胺之乙酸鹽（3〇9毫Anhydrous vaporized hydrazine (111) (557 g, 22.6 mM millimolar) and anhydrous tetrahydrofuran (20 ml) were added to a water-free 2-neck round bottom flask under nitrogen. Make the resulting hanging π main vision scale about y ϋ minutes. Slowly add methyl lithium (14·13 ml, 22.603⁄4 mol for about 6 min and warm to about, then cool the reaction to -5 (TC, and add 4_(3-(3_气_4) _Isopropoxyphenyl, 'oxadiazol-5-yl)benzonitrile (2.4 g, 7_〇6 mmol) 8 ml of anhydrous τΗρ, maintaining the reaction temperature at about _5 (TC. Maintained in a clever way: lasts for an hour, then warms it to ambient temperature overnight. The next day the reaction is cooled to _5 〇 °c, and the reaction is terminated by adding 21 ml of 35% ΝΗ4〇ί^$. Anti-127788.doc -134- 200840567 should be warmed to room temperature for two days. The mixture was filtered through Celite® and washed with DCM (4×60 mL). The filtrate was collected and then washed with water and dehydrated with MgSCU. The crude product was subjected to Rp_HPLC (A=50 mM ammonium acetate, acetonitrile; 30-70% B for 30·0 minutes (flow rate 21.03⁄4 liters/min), 21.2×250^; Thermo Hyper prep C18 column, 8 μπ^ Purification to obtain 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-0-di-n-5-yl)phenyl)propane-2 -amine acetate (3〇9 毫

克 ’ 10.1%)。LCMS(表 1 ’ 方法 a) Rt=2.61 min; ^ NMR克 ' 10.1%). LCMS (Table 1 'Method a) Rt = 2.61 min; ^ NMR

(400 MHz, DMSO-d6) δ ppm 8.14-7.94 (m? 4H), 7.80 (d J=8.43 Hz，2H)，7.37 (d，J=8.81 Hz，1H)，4.80 (sept，J=6.04 Hz，1H)，1.85 (s，3H)，1.39 (s，6H)，1·36-1·31 (d，J=6.04(400 MHz, DMSO-d6) δ ppm 8.14-7.94 (m? 4H), 7.80 (d J=8.43 Hz, 2H), 7.37 (d, J=8.81 Hz, 1H), 4.80 (sept, J=6.04 Hz) ,1H),1.85 (s,3H),1.39 (s,6H),1·36-1·31 (d,J=6.04

Hz，6H)。 實例編號8 : 3-(2·(4-(3-(3氣-4-異丙氧基苯基）β1，2,4_嘮二 唑-5-基）苯基）丙-2-基胺基）丙睃甲酯之製備Hz, 6H). Example No. 8: 3-(2·(4-(3-(3)-4-isopropoxyphenyl)β1,2,4-oxadiazol-5-yl)phenyl)propan-2-yl Preparation of Amino) Methyl Acetate

將2-(4-(3-(3-氣-4-異丙氧基苯基）_ι，2,4-σ号二tr坐_5_基）笨 基）丙烷-2-胺及乙酸（132毫克，〇·3〇6毫莫耳）添加於裝置有 授摔棒之5宅升微波樂瓶中。添加丙婦酸甲醋（$ 2 · $毫克。 0.611毫莫耳）及MeOH(3.0毫升），將藥瓶蓋住且使反應在 微波幅射（Biotage Optimizer，300 W)下加熱至約12〇。〇歷時 約90分鐘。約90分鐘後，添加另一份丙烯酸甲酯（52·6毫 克’ 〇·611毫莫耳）且使反應在約i2〇°c下再加熱60分鐘。使 127788.doc -135· 200840567 反應冷卻且減壓移除溶劑。使粗製物質經rP_Hplc(A=50 mM乙酸銨，B=乙腈；30-70% B歷時30.0分鐘（流速21.0毫 升 / 分鐘），21.2x250 mm Thermo Hyperprep C18 管柱，8μηι 粒子）純化，獲得3-(2-(4-(3-(3-氣·4-異丙氧基苯基）-ΐ，2,4-吟一峻-5-基）苯基）丙-2-基胺基）丙酸甲酯（83 5毫克， 59.7%)。LCMS(表 1，方法 a) Rt=2 78 min，w/z=458 29 (M=H)+ 〇 實例編號9 : 3-(2-(4-(3-(3-氣異丙氧基苯基号二 嗅-5-基）苯基）丙_2_基胺基）丙酸之製備2-(4-(3-(3-Gas-4-isopropoxyphenyl)_ι, 2,4-σ-di-tr _5-yl) phenyl)propan-2-amine and acetic acid ( 132 mg, 〇·3〇6 mmoles) was added to the 5 liter microwave bottle of the device. Add methyl acetoacetate ($2. $mg. 0.611 mmol) and MeOH (3.0 mL), cover the vial and heat the reaction to about 12 在 under microwave radiation (Biotage Optimizer, 300 W). . It takes about 90 minutes. After about 90 minutes, another portion of methyl acrylate (52. 6 mg &lt;RTI ID=0.0&gt;&gt; The reaction was allowed to cool 127788.doc - 135 · 200840567 and the solvent was removed under reduced pressure. The crude material was purified by rP_Hplc (A=50 mM ammonium acetate, B=acetonitrile; 30-70% B for 30.0 minutes (flow rate 21.0 ml/min), 21.2 x 250 mm Thermo Hyperprep C18 column, 8 μηι particles). (2-(4-(3-(3-)-isopropoxyphenyl)-fluorene, 2,4-indolyl-5-yl)phenyl)propan-2-ylamino)propyl Methyl ester (83 5 mg, 59.7%). LCMS (Table 1, Method a) Rt = 2 78 min, w/z = 458 29 (M = H) + 〇 Example No. 9: 3-(2-(4-(3-(3-isopropoxy)) Preparation of Phenyldiol-5-yl)phenyl)propan-2-amino)propionic acid

使3-(2-(4-(3-(3-氯-4-異丙氧基苯基）_ι，2,4-呤二唑-5-基） 苯基）丙-2·基胺基）丙酸曱酯（83毫克，〇181毫莫耳）溶於乙 醇（4毫升）中且添加NaOH(4毫升，8 〇〇毫莫耳）。使混合物 在室溫下及氮氣中攪拌。約2〇分鐘後，滴加乙酸中和反 應。接著使水性混合物冷凍並凍乾。於固體中添加DCm， 經過濾且以DCM洗滌。濃縮濾液且添加乙醚獲得稍混濁之 溶液。滴加1 N HC1之乙醚直到形成白色沉澱物為止。過 濾收集該物質，以乙醚洗滌且真空乾燥，獲得3_(2_(4_(3胃 (3_氯異丙氧基苯基）-1，2,4-嘮二唑-5-基）苯基）丙-2-基胺 基）丙酸之鹽酸鹽（61·5毫克；70.6%)。LCMS(表1，方法a) Rt=1.98 min? m/z=444.29 (M=H)+; lU NMR (400 MHz, DMSO-d6) δ ppm 8·32 (d，J=8.57 Hz，2H)，8.12 (d，J=2.08 127788.doc -136- 2008405673-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)), 2,4-oxadiazol-5-yl)phenyl)propan-2-ylamino The decyl propionate (83 mg, 〇181 mmol) was dissolved in ethanol (4 mL) and NaOH (4 mL, 8 〇〇m) was added. The mixture was stirred at room temperature under nitrogen. After about 2 minutes, the acetic acid was neutralized. The aqueous mixture is then frozen and lyophilized. DCm was added to the solid, filtered and washed with DCM. The filtrate was concentrated and diethyl ether was added to give a slightly turbid solution. 1 N HCl in diethyl ether was added dropwise until a white precipitate formed. The material was collected by filtration, washed with diethyl ether and dried in vacuo to give &lt;RTI ID=0.0&gt;&gt; Hydrochloride of propan-2-ylamino)propionic acid (61.5 mg; 70.6%). </ RTI> <RTIgt; , 8.12 (d, J=2.08 127788.doc -136- 200840567

Hz，1H)，8.03 (dd，J=8.64，2·10 Hz，1Η)，7·85 (d，J=8.59 Hz，2H)，7.25 (d，J=8.78 Hz，1H), 4.79 (sept，J=6.11 Hz， 1H)，2.95 (t，J=6.20 Hz，2H)，2.44 (t，J=6.17 Hz，2H)，1·84 (s，6H)，1·40 (d，j = 6 〇4 Hz，6H)。 實例編號10 : 3-(3-氣-4-異丙氧基苯基）-5-(lH-吲哚-4-基）-1，2,4_〃号二唑之製備Hz, 1H), 8.03 (dd, J=8.64, 2·10 Hz, 1Η), 7.85 (d, J=8.59 Hz, 2H), 7.25 (d, J=8.78 Hz, 1H), 4.79 (sept , J=6.11 Hz, 1H), 2.95 (t, J=6.20 Hz, 2H), 2.44 (t, J=6.17 Hz, 2H), 1.84 (s, 6H), 1·40 (d, j = 6 〇 4 Hz, 6H). Example No. 10: Preparation of 3-(3-cyclo-4-isopropoxyphenyl)-5-(lH-indol-4-yl)-1,2,4-oxadiazole

在氮氣中使含1H-吲哚-4-曱酸（3.88克，24.05毫莫耳）、 (3-二甲胺基-丙基 &gt; 乙基-碳二醯亞胺鹽酸鹽（4·6ι克，24〇5 宅莫耳）及苯并三唑-1-醇水合物（3·68克，24.05毫莫耳）之 無水DMF(61.4毫升）混合物在周圍溫度下攪拌約1小時。於 反應混合物中添加含3-氣羥基-4-異丙氧基苯曱脒（5.〇 克’ 21.87¾莫耳）之DMF(11.51毫升）溶液。使混合物在約 140 C下攪拌約2小時。使混合物冷卻至周圍温度且倒入水 (1升）中。使產物分溶於乙酸乙酯及水相中。有機層以1 N HC1 (4x150 毫升）、1 N NaOH(2xl50 毫升）及水（2x300 毫升） 洗務，以MgS〇4脫水並過滤。減壓移除溶劑且使粗製產物 經Florisil，以庚烷/乙酸乙酯（2:1)溶離純化，獲得、（、氣― 4-異丙氧基本基）-5-(111-11弓丨11朵-4-基）-1，2,4*^号二峻（2.76克， 35.7°/。)。LCMS(表 1，方法b) Rt=2.69 min，m/z 354.17 (M+H)+。 實例編號11 : (4_(3·(3_氣-4_異丙氧基苯基 127788.doc -137· 200840567 基）苯基）甲醇之製備1H-indole-4-decanoic acid (3.88 g, 24.05 mmol), (3-dimethylamino-propyl) ethyl-carbodiimide hydrochloride (4·) Mixture of 6 gram, 24 〇 5 house Moer) and benzotriazol-1-ol hydrate (3·68 g, 24.05 mmol) in anhydrous DMF (61.4 ml) was stirred at ambient temperature for about 1 hour. A solution of 3-methoxyhydroxy-4-isopropoxyphenylhydrazine (5. gram ' 21.873 Å moles) in DMF (11.51 mL) was added to the reaction mixture. The mixture was stirred at about 140 C for about 2 hours. The mixture was cooled to ambient temperature and poured into water (1 liter). The product was partitioned between ethyl acetate and water. The organic layer was taken to 1 N EtOAc (4×150 mL), 1 N NaOH (2×l 50 mL) and water ( 2×300 ml), dehydrated and filtered with MgS〇4. The solvent was removed under reduced pressure and the crude product was purified by Florisil eluting with heptane/ethyl acetate (2:1) to obtain ( Propyloxy)-5-(111-11 丨11-4-yl)-1,2,4*^ No.2 (2.76 g, 35.7 °/.) LCMS (Table 1, Method b) Rt=2.69 min, m/z 354.17 (M+H)+. Example No. 11: (4_(3·( Preparation of 3_gas-4_isopropoxyphenyl 127788.doc -137· 200840567 base) phenyl)methanol

於含4-(羥基曱基）苯曱酸（〇 220克，ι·443毫莫耳）之 DMF(1.640毫升）漿料中添加EDC(0.277克，1.443毫莫 耳），接著添加HOBT水合物（0.195克，1.443毫莫耳）。約 45分鐘後，添加含氣_N，-羥基-4-異丙氧基本甲脒 (0.300克，1.31毫莫耳）之DMF(1.640毫升）溶液且使反應混 合物加熱至約140°C歷時約2小時。冷卻至室溫後，真空濃 縮反應混合物且在矽膠上進行層析（以EtOAc/庚烷溶離）純 化，獲得灰白色固體之（4-(3-(3-氣-4-異丙氧基苯基）4,2,‘ 崎二唑-5-基）苯基）甲醇（0.336克，71%)。LCMS(表1，方法 c) Rt=2.80 min，m/z 345 (Μ+Η)+。 實例編號12 : 5-(4-(疊氮基曱基）苯基）-3-(3-氣_4_異丙氧基 苯基）_1，2,4·嘮二唑之製備Add EDC (0.277 g, 1.443 mmol) to a slurry of 4-(hydroxyindenyl)benzoic acid (〇220 g, ι·443 mmol) in DMF (1.640 mL), followed by HOBT hydrate (0.195 g, 1.443 mmol). After about 45 minutes, a solution of gas-_N,-hydroxy-4-isopropoxybenzamide (0.300 g, 1.31 mmol) in DMF (1.640 mL) was added and the reaction mixture was heated to about 140 ° C for about 2 hours. After cooling to room temperature, the reaction mixture was purified mjjjjjjjjjjjjj 4,2, 'Soxadiazol-5-yl)phenyl)methanol (0.336 g, 71%). LCMS (Table 1, Method c) Rt = 2.80 min, m/z 345 ( Μ + Η) +. Example No. 12: Preparation of 5-(4-(azidoindolyl)phenyl)-3-(3-gas-4-isopropoxyphenyl)_1,2,4.oxadiazole

於含（4-(3-(3 -氯-4-異丙氧基苯基）-1，2,4-口号二嗤-5-基）苯 基）曱醇（0.100克，0.290毫莫耳）之THF( 1.5毫升）溶液中添 加DBU(0.048毫升，〇·319毫莫耳），接著添加疊氮磷酸二 苯酯（0·069毫升，〇·319毫莫耳）。約15小時後，將反應混 合物倒入乙醚及飽和NaHC〇3中。分離有機層，以鹽水洗 127788.doc -138- 200840567 滌，經脫水（MgSCU)，真空濃縮且在矽膠上進行層析（以 EtOAc/庚烷溶離）純化，獲得5_(4气疊氮基曱基）苯基）_3_(3_ 氯-4-異丙氧基苯基）-1，2,4-噚二唑（〇〇66克，6〇%)之無色固Containing (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadicin-5-yl)phenyl) decyl alcohol (0.100 g, 0.290 mmol) DBU (0.048 ml, 〇·319 mmol) was added to a solution of THF (1.5 mL), followed by diphenyl azide (0. 069 mL, 319·319 mmol). After about 15 hours, the reaction mixture was poured into diethyl ether and saturated NaHC. The organic layer was separated, washed with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. Colorless solid of phenyl)phenyl)_3_(3_chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (〇〇66 g, 6〇%)

體。LCMS(表 1，方法 c) Rt=3.22 min，m/z 370 (M+H)+。 實例編號13.(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-吟二峻_ 5_基）苯基）曱胺之製備body. LCMS (Table 1, Method c) Rt = 3.22 min, m/z 370 (M+H)+. Example No. 13. Preparation of 4-(3-(3-(3-oxa-4-isopropoxyphenyl)-1,2,4-fluorenyl)-5-phenyl)decylamine

於含5-(4-(疊氮基甲基）苯基）-3-(3-氣-4-異丙氧基苯基）-1，2,4-嘮二唑（〇·〇66克，0.178毫莫耳）之THF(3.40毫升）及水 (0.170毫升）溶液中添加聚合物支撐之三苯基膦（0.237克， 〇·711毫莫耳）。約2小時後，使反應混合物加熱至約60°C。Containing 5-(4-(azidomethyl)phenyl)-3-(3-ce-4-isopropoxyphenyl)-1,2,4-oxadiazole (〇·〇66g) Polymer-supported triphenylphosphine (0.237 g, 711·711 mmol) was added to a solution of 0.178 mmol of THF (3.40 mL) and water (0.170 mL). After about 2 hours, the reaction mixture was heated to about 60 °C.

約1小時後，使反應混合物冷卻至室溫，經過濾，真空濃 縮且在矽膠上進行層析（以MeOH:DCM溶離）純化，獲得無 色固體之（4-(3-(3-氣-4·異丙氧基苯基号二唑-5-基） 苯基）曱胺（40毫克，64%)。 LCMS(表 1，方法 c) r尸ι·97 min，m/z 344 (M+H)+。 製備例編號1 : 3-(3-(3-氣-4-異丙氧基苯基）·1，2,4-噚二唑-5-基）環戊酮After about 1 h, the reaction mixture was cooled to EtOAc (EtOAc m. · Isopropoxyphenyl diazol-5-yl) phenyl) decylamine (40 mg, 64%). LCMS (Table 1, Method c) r s ι·97 min, m/z 344 (M+ H) +. Preparation No. 1: 3-(3-(3-Ga-4-isopropoxyphenyl)·1,2,4-oxadiazol-5-yl)cyclopentanone

於含3-側氧基環戊烷甲酸（0.123克，〇·962毫莫耳）之 127788.doc -139- 200840567 DMF(1.0毫升）漿料中添加EDC((M84克，0·962毫莫耳）， 接著添加HOBt水合物（0.1 30克，0.962毫莫耳）。約1小時 後，添加含（Z)-3-氯-Ν’-羥基-4-異丙氧基苯甲肺（〇·2克， 0.875毫莫耳）之DMF(0.5毫升）溶液且使反應混合物加熱至 約140°C歷時約45分鐘。冷卻至室溫後，真空濃縮反應混 合物且在矽膠上進行層析（以Et0Ac/庚烷溶離）純化，獲得 黃色油之3-(3-(3-氯-4-異丙氧基苯基）-1，2,4-嘮二唑-5-基） 環戊酮（0.156 克，56%)。LCMS(表 1，方法 c) Rt=2.75 min， m/z 321 (Μ+Η)+ 〇 製備例編號2 : 3-(3-(3·(3·氯-4-異丙氧基苯基）-ΐ，2,4-噚二 嗤-5-基）環戊基胺基）丙酸Add EDC ((M84 g, 0·962 mmol) to the 127788.doc-139-200840567 DMF (1.0 ml) slurry containing 3-oxooxycyclopentanecarboxylic acid (0.123 g, 〇·962 mmol) Ear), then add HOBt hydrate (0.1 30 g, 0.962 mmol). After about 1 hour, add (Z)-3-chloro-indole-hydroxy-4-isopropoxybenzene (p) 2 g, 0.875 mmol of DMF (0.5 ml) solution and the reaction mixture was heated to about 140 ° C for about 45 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo and chromatographed on silica gel Purification by Et0Ac / heptane elution to give 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone as a yellow oil. 0.156 g, 56%). LCMS (Table 1, Method c) Rt = 2.75 min, m/z 321 (Μ + Η) + 〇 Preparation Example No. 2: 3-(3-(3·(3·chloro-4) -isopropoxyphenyl)-indole, 2,4-indenyl-5-yl)cyclopentylamino)propionic acid

於含3-(3-(3-氣-4-異丙氧基苯基）-1，2,4-吟二唑-5-基）環 戊酮（0·178克，0.555毫莫耳）之MeOH(6.94毫升）及 DCE(6.94毫升）漿料中添加乙酸（〇·254毫升，4.44毫莫 耳），接著添加3-胺基丙酸（0.494克，5,55毫莫耳）。1小時 後，於反應混合物中添加氰基硼氫化鈉（0.017克，0.277毫 莫耳）。約1 5小時後，過慮反應混合物，以MeOH洗滌。真 空濃縮濾液且以RP HPLC純化，獲得3-(3-(3-(3-氯-4-異丙 氧基苯基）-1，2,4-崎二唑-5-基）環戊基胺基）丙酸。LCMS(表 1，方法 c) Rt=1.64 min，m/z 394 (M+H)+。 製備例編號3 : 4-(3-(3-(3-氣-4·異丙氧基苯基）-12,4-哼二 127788.doc -140· 200840567 唑-5-基）環戊基胺基）丁酸Containing 3-(3-(3- gas-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone (0·178 g, 0.555 mmol) Acetic acid (〇·254 ml, 4.44 mmol) was added to the MeOH (6.94 mL) and DCE (6.94 mL), and then 3-aminopropionic acid (0.494 g, 5,55 mmol) was added. After 1 hour, sodium cyanoborohydride (0.017 g, 0.277 mmol) was added to the mixture. After about 15 hours, the reaction mixture was taken up and washed with MeOH. The filtrate was concentrated in vacuo and purified by EtOAc to afford 3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentyl Amino) propionic acid. LCMS (Table 1, Method c) Rt = 1.64 min, m/z 394 (M+H)+. Preparation No. 3: 4-(3-(3-(3-Gas-4.isopropoxyphenyl)-12,4-anthracene 127788.doc -140· 200840567 oxazol-5-yl)cyclopentyl Amino)butyric acid

N-0N-0

i^&gt;0 HO 使3-(3-(3-氯-4·異丙氧基苯基）_1，2,4_啰二唑-5-基）環戊I^&gt;0 HO makes 3-(3-(3-chloro-4.isopropoxyphenyl)_1,2,4-oxadiazol-5-yl)cyclopentane

酮（0.078克，0.243毫莫耳）懸浮於MeOH(3.〇4毫升）及DCEKetone (0.078 g, 0.243 mmol) suspended in MeOH (3. 4 mL) and DCE

(3 ·04毫升）之混合物中。於該混合物中添加乙酸（〇· 1丨1毫 升，1.945毫莫耳）接著添加固體4-胺基丁酸（〇·251克， 2.432毫莫耳）。使溶液在室溫下攪拌〇·5-1小時。接著一次 添加氰基硼氫化鈉（7.46毫克，0.122毫莫耳）。使反應在室 溫下攪拌隔夜且經LCMS顯示反應已完全。濾除過量胺基 酸且真空濃縮濾液。使粗製油分溶於乙酸乙酯及鹽水中。 有機層經脫水（MgS04)及濃縮，獲得殘留物，該殘留物在 Prep HPLC 系統上使用含 3〇-1〇〇〇/0 ACN之 50 mM NH4OAc緩 衝液，以21毫升/分鐘純化，合併第12-14溶離份且真空濃 縮。使所得物質於MeOH中經超音波。過濾懸浮之沉澱 物’以MeOH洗滌且乾燥，獲得白色固體之4_(3_(3_(3_氯_ 4-異丙氧基苯基噚二唑-5-基）環戊基胺基）丁酸（u 毫克 ’ 0.025 毫莫耳）。LCMS(表 1，方法 c) Rt=1.72 min， m/z 408.22 (M-H)+。4 NMR (400 MHz，DMSO) δ ppm 8·06_7·94 (d，2H)，7.89-7.79 (dd，J=1.99，8·66 Hz，1H)， 7·14_7·06 (d，J = 8.68 HZ，1H)，4.78-4.65 (td，J=6.08，12.13 Hz，1H)，4·09·3·96 (dd，J=5.94，10.14 Hz，1H)，3.91-3.79 (m，1H)，3.38-3.24 (t，J=7.26 Hz，2H)，2.73-2.65 (dd， 127788.doc -141 - 200840567 J=4.81 11.44 Hz，2H)，2·65-2·56 (m，ΐΗ)，2·53-2·37 (m， 2H)，2·37-2·28 (m，1H)，2·28·2·22 (m，1H)，2.22-2.20 (s， 1H)，2.20-2.10 (m，2H)，[2·1〇_ι·96 (m，m) andl 48138 (d，J=6.05 Hz，6H) 〇 製備例編號4 · 4-((2,2·二甲基，夂二氧雜環戊_4_基）甲氧 基)苯甲酸（R)-苄酯In a mixture of (3 · 04 ml). Acetic acid (〇·1丨1 ml, 1.945 mmol) was added to the mixture followed by the addition of solid 4-aminobutyric acid (〇·251 g, 2.432 mmol). The solution was allowed to stir at room temperature for 5-1 hours. Sodium cyanoborohydride (7.46 mg, 0.122 mmol) was then added in one portion. The reaction was allowed to stir at room temperature overnight and the reaction was completed by LCMS. The excess amino acid was filtered off and the filtrate was concentrated in vacuo. The crude oil was dissolved in ethyl acetate and brine. The organic layer was dehydrated (MgS04) and concentrated to give a residue, which was purified on a Prep HPLC system using 50 mM NH4OAc buffer containing 3〇-1〇〇〇/0 ACN at 21 ml/min. The fractions were dissolved in 12-14 and concentrated in vacuo. The resulting material was subjected to ultrasonication in MeOH. The suspended precipitate was filtered and washed with MeOH and dried to give 4-(3-(3-(3-chloro-4-isopropoxyphenyloxadiazol-5-yl)cyclopentylamino)butyric acid as a white solid. (u mg '0.025 mM) LCMS (Table 1, Method c) Rt = 1.72 min, m/z 408.22 (MH) +. 4 NMR (400 MHz, DMSO) δ ppm 8·06_7·94 (d, 2H), 7.89-7.79 (dd, J=1.99, 8.66 Hz, 1H), 7·14_7·06 (d, J = 8.68 HZ, 1H), 4.78-4.65 (td, J=6.08, 12.13 Hz, 1H), 4·09·3·96 (dd, J=5.94, 10.14 Hz, 1H), 3.91-3.79 (m, 1H), 3.38-3.24 (t, J=7.26 Hz, 2H), 2.73-2.65 ( Dd, 127788.doc -141 - 200840567 J=4.81 11.44 Hz, 2H), 2·65-2·56 (m, ΐΗ), 2·53-2·37 (m, 2H), 2·37-2· 28 (m,1H),2·28·2·22 (m,1H), 2.22-2.20 (s, 1H), 2.20-2.10 (m,2H),[2·1〇_ι·96 (m, m) andl 48138 (d, J = 6.05 Hz, 6H) 〇 Preparation No. 4 · 4-((2,2·Dimethyl, indoledioxol-4-yl)methoxy)benzoic acid ( R)-benzyl ester

於250¾升圓底瓶中添加含三笨基膦（6·54克，24 92毫莫 耳）之THF(79毫升），獲得無色澄清溶液。以冰浴使該溶液 冷卻至0 C。攪拌15分鐘後，於5分鐘内滴加疊氮二甲酸二 異丙酯(5.11毫升，24.96毫莫耳)(橘色液體）。反應混合物 於該過程中轉變成灰白色懸浮液。使反應混合物在〇。〇下 攪拌30分鐘。接著於該混合物中添加含4_羥基苯甲酸苄酯 (5.69克，24.92毫莫耳）及^)_(2,2_二甲基_1，3_二氧雜環戊-4-基）甲醇（3.00毫升，23·73毫莫耳）之THF(39 5毫升）無色 溶液’使溫度維持在低於〇°c。溶液變成透明淡黃色。使 /谷液在0 C下攪拌2小時，接著緩慢升溫至周圍溫度且擾拌 隔一週末。真空濃縮反應混合物，獲得粗製黃色油（約27 克）。使粗製油溶於乙_中。接著添加庚烧。使所得沉殺 物經超音波並過濾。濃縮濾液且經Anai〇gix系統純化，使 用RediSep RS 120 g管柱，以0-20% EtOAc/庚烷之梯度在 127788.doc -142- 200840567 50¾升/分鐘下歷時1〇分鐘，接著維持在2〇Q/。乙酸乙酯下2〇 分鐘。合併含產物之溶離份且濃縮，獲得白色固體之‘ ((2,2-二曱基-1，3-二氧雜環戊基）曱氧基）苯曱酸苄酯 (6·17克，23·73毫莫耳）。LCMS(表 1，方法c) Rt=2.89 min， m/z 343.20 (M+H)+ 〇 製備例編號5 : (R)-4_((2,2-二甲基_i，3_二氧雜環戊_4_基）甲 氧基）苯甲酸To a 2503⁄4 liter round bottom flask was added THF (79 ml) containing trisylphosphine (6. 54 g, 24 92 mmol) to give a colorless, clear solution. The solution was cooled to 0 C in an ice bath. After stirring for 15 minutes, diisopropyl azide dicarboxylate (5.11 ml, 24.96 mmol) (orange liquid) was added dropwise over 5 minutes. The reaction mixture was converted to an off-white suspension during the process. The reaction mixture was allowed to dry. Stir under the arm for 30 minutes. Then, benzyl 4-hydroxybenzoate (5.69 g, 24.92 mmol) and ^)_(2,2-dimethyl-1,3-dioxol-4-yl) were added to the mixture. Methanol (3.00 mL, 23.73 mmol) in THF (39 5 mL) mp. The solution turned transparent and pale yellow. The / gluten solution was stirred at 0 C for 2 hours, then slowly warmed to ambient temperature and disturbed for one weekend. The reaction mixture was concentrated in vacuo to give a crude yellow oil (~27 g). The crude oil was dissolved in B_. Then add heptane. The resulting sink is ultrasonicated and filtered. The filtrate was concentrated and purified on an EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 2〇Q/. Under ethyl acetate for 2 minutes. The product-containing fractions were combined and concentrated to give benzyl ((2,2-didecyl-1,3-dioxo) methoxy)benzoic acid as a white solid (6·17 g, 23·73 millimoles). LCMS (Table 1, Method c) Rt = 2.89 min, m/z 343.20 (M+H) + 〇 Preparation Example No. 5: (R)-4_((2,2-Dimethyl-i,3-diox Heterocyclic pent-4-yl)methoxy)benzoic acid

於500毫升高壓瓶中饋入鈀/碳（0·300克，0 282毫莫耳）， 接著添加MeOH(200毫升），接著添加4-((2,2-二甲基-ΐ，3-二 氧雜環戊-4-基）曱氧基）苯甲酸（R)_苄酯（6·17克，i8〇2毫莫 耳）。使所得懸浮液在氫氣（35 psi)及周圍壓力下搖晃2小 時。使混合物經Celite®過濾且濃縮無色濾液，獲得白色固 體之（R)-4-((2,2-二甲基-1，3-二氧雜環戊-4-基）曱氧基）苯甲 酸（4.45克，17.64毫莫耳）。LCMS(表1，方法c) R产2 15 min，w/z 253.14 (M+H)+ 〇 製備例編號6 : (R)-3-(3-氣-4-異丙氧基苯基）-5-(4_((2,2_二 甲基·1，3-二氧雜環戊-4-基）甲氧基）_ι，2,4·噚二唑 127788.doc -143 - 200840567Palladium/carbon (0.300 g, 0 282 mmol) was fed into a 500 ml autoclave, followed by MeOH (200 mL) followed by 4-((2,2-dimethyl-indole, 3- (R)-benzyl ester of dioxol-4-yl) decyloxy)benzoic acid (6.91 g, i8 〇 2 mmol). The resulting suspension was shaken under hydrogen (35 psi) and ambient pressure for 2 hours. The mixture was filtered through Celite® and the colourless filtrate was concentrated to afford (R)-4-((2,2-dimethyl-l-1,3-dioxo-4-yl) methoxy)benzene as a white solid. Formic acid (4.45 g, 17.64 mmol). LCMS (Table 1, Method c) R yield 2 15 min, w/z 253.14 (M+H) + 〇 Preparation Example No. 6: (R)-3-(3-A. -5-(4_((2,2-dimethyl-1,3-1,3-dioxo-4-yl)methoxy)_ι,2,4·oxadiazole 127788.doc -143 - 200840567

於含（R)-4-((2,2_二甲基_;ι，3_二氧雜環戊-4_基）甲氧基）苯 甲酸（0.303克，1.203毫莫耳）之DMF(1.367毫升）漿料中添 加EDC(0.23 1克，1.203毫莫耳），接著添加H〇BT水合物 (0.163克，1.203 ¾莫耳）。約ι·5小時後，添加含（2)_3_氣_ Ν’-經基-4·異丙氧基苯甲脉（0.250克，ΐ·〇9毫莫耳）之 DMF(1 · 3 67宅升）溶液。使反應混合物加熱至14〇歷時約2 小時。冷卻至室溫後，真空濃縮反應混合物且在矽膠上進 行層析（以EtOAc/庚烷溶離）純化，獲得無色固體之（R)_3_ (3 -氣-4-異丙氧基本基）-5-(4-((2，2-二甲基_1，3-二氧雜環戊_ 4-基）曱氧基）-1，2,4-口号二唑（〇·339 克，70%)。LCMS(表 1， 方法 c) Rt=3.36 min，m/z 445 (Μ+Η)+。 實例編號14 · (S)-3-(4-(3-(3·氣-4-異丙氧基苯基）4,2,4·崎 二唑-5 ·基)苯氧基）丙烷_ i，2 -二醇之製備DMF containing (R)-4-((2,2-dimethyl-; ι,3-dioxol-4-yl)methoxy)benzoic acid (0.303 g, 1.203 mmol) (1.367 ml) EDC (0.23 g, 1.203 mmol) was added to the slurry followed by H〇BT hydrate (0.163 g, 1.203 3⁄4 mol). After about 5 hours, DMF (1 · 3 67) containing (2) _3_gas _ Ν '- keto-4·isopropoxy benzophenone (0.250 g, ΐ·〇 9 mmol) was added. House liter) solution. The reaction mixture was heated to 14 Torr for about 2 hours. After cooling to room temperature, the reaction mixture was purified mjjjjjjjjjjjjjjjj -(4-((2,2-dimethyl-1,3-dioxol-4-yl)decyloxy)-1,2,4-oxadiazole (〇·339 g, 70% LCMS (Table 1, Method c) Rt = 3.36 min, m/z 445 (Μ + Η) +. Example No. 14 · (S)-3-(4-(3-(3·气-4-) Preparation of propoxyphenyl) 4,2,4·soxadiazol-5·yl)phenoxy)propane _ i,2-diol

於S (R)-3-(3-氣-4-異丙氧基笨基）-5-(4-((2 2- -甲基· 1，3_二氧雜環戊-4-基）曱氧基）-1，2,4-吟二唑（〇 339克， 〇_762毫莫耳）之thF(15.24毫升）溶液中添加1 N HC1溶液 (1·524毫升，毫莫耳）。48小時後，添加額外之！ n 127788.doc -144 - 200840567 HCl (2.286毫升，2·286毫莫耳）且使反應混合物加熱至7〇。〇 歷時2小時。冷卻至周圍溫度後，添加丨N Na〇H溶液（381 毫升，3.81毫莫耳）且真空濃縮反應混合物。所得固體以大 ϊ水洗條且真空乾燥，獲得無色固體之（§)-3_(4_(3_(3_氣_ 4-異丙氧基苯基）4,2,4-呤二唑基）苯氧基）丙烷二醇 (0.294克，94%)。LCMS(表 i，方法c)Rt=2.73 min，_4〇5 (M+H)+ 〇 實例編號15:4-(3-(3-氣-4-異丙氧基苯基）_1，2,4_，号二嗤-5-基）苯磺醯胺之製備S(R)-3-(3-Gas-4-isopropoxy)-5-(4-((2 2-methyl-) 1, 3-dioxol-4-yl Add 1 N HCl solution (1·524 ml, millimolar) to a solution of 曱oxy)-1,2,4-oxadiazole (〇339 g, 〇_762 mmol) in thF (15.24 ml) After 48 hours, add extra! n 127788.doc -144 - 200840567 HCl (2.286 ml, 2.286 mmol) and heat the reaction mixture to 7 〇. 〇 lasts for 2 hours. After cooling to ambient temperature, add丨N Na〇H solution (381 mL, 3.81 mmol) and the reaction mixture was concentrated in vacuo. The obtained solid was washed with water and dried in vacuo to give a colorless solid ( s) -3 _ _ _ _ _ _ 4-isopropoxyphenyl) 4,2,4-oxadiazolyl)phenoxy)propanediol (0.294 g, 94%). LCMS (Table i, Method c) Rt = 2.73 min, _4 〇 5 (M+H)+ 〇Example No. 15: 4-(3-(3-Gas-4-isopropoxyphenyl)_1,2,4_,dioxa-5-yl)benzenesulfonamide preparation

於含4-胺磺醯基苯甲酸（1.452克，7.22毫莫耳）之DMF (8.20毫升）漿料中添加EDC(1.383克，7.22毫莫耳）接著添 加HOBT水合物（0.975克，7.22毫莫耳）。約30分鐘後，添 加含（Z)-3-氣-N，-羥基-4-異丙氧基苯甲脒之DMF(8.2毫升） 溶液。使反應混合物加熱至約140°C歷時約2小時。冷卻至 室溫後，真空濃縮反應混合物且在矽膠上進行層析（以 EtOAc/庚烷溶離）純化，獲得無色固體之4-(3-(3-氣-4-異丙 氧基苯基）-1，2,4-号二峻-5-基）苯續醯胺（1.28克，50%)。 LCMS(表 1，方法 c) Rt=2.74 min，m/z 392 (M-Η)· 〇 實例編號16 : 3，3,- (4-(3-(3 -氣-4-異丙氧基苯基）-1，2，4-崎二 峻-5·基）苯基確醯基氮二基（azanediyl))二丙酸第三丁酯及 127788.doc -145- 200840567 3-(4-(3-(3-氣-4-異丙氧基苯基）-ΐ，2,4·〃号二嗤-5-基）苯基確 醯胺基)丙酸第三丁酯之製備EDC (1.383 g, 7.22 mmol) was added to a slurry of 4-aminosulfonylbenzoic acid (1.452 g, 7.22 mmol) in DMF (8.20 mL) followed by HOBT hydrate (0.975 g, 7.22 m) Moore). After about 30 minutes, a solution of (Z)-3- gas-N,-hydroxy-4-isopropoxybenzamide in DMF (8.2 mL) was added. The reaction mixture was heated to about 140 ° C for about 2 hours. After cooling to room temperature, the reaction mixture was evaporated mjjjjjjjjjjjjj -1,2,4-di-bi-5-yl)benzene decylamine (1.28 g, 50%). LCMS (Table 1, Method c) Rt = 2.74 min, m/z 392 (M - Η) · 〇 Example No. 16: 3,3,- (4-(3-(3-)-isopropoxy Phenyl)-1,2,4-azakidi-5-yl)phenyl azanediyl)dibutyl phthalate and 127788.doc -145- 200840567 3-(4- Preparation of (3-(3-gas-4-isopropoxyphenyl)-anthracene, 2,4·〃-di-n-5-yl)phenyl-decylamino)propionic acid tert-butyl ester

於含4-(3-(3 -氯-4 -異丙氧基苯基）-1，2,4·号二。坐-5-基）苯石黃 醯胺（0.500克，1.270毫莫耳）之DMF(3.17毫升）溶液中添加 NaH(0.0 5 6克’ 1 · 3 9 6宅莫耳）。約1 〇分鐘後，添加3 -臭丙酸 第三丁酯（0.233毫升，1.396毫莫耳）且使反應混合物加熱 至約6(TC。約48小時後，使反應混合物冷卻至室溫且在石夕 膠上進行層析（以EtOAc/庚烧溶離）純化，獲得無色固體之 3,3f-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-，号二哇-5-基）苯基 磺醯基氮二基）二丙酸第三丁酯（0.24克，29%)。LCMS(表 1，方法 c) Rt=3.43 min，m/z 667 (M+NH4)+ 〇 此夕卜，獲得無 色固體之3-(4-(3-(3-氣-4-異丙氧基笨基）-1，2,4-嘮二唑-5-基）苯基磺醯胺基）丙酸第三丁酯（0.28克，42%)。LCMS(表 1，方法c) Rt=3.13 min，m/z 521 (M-Η)· 〇 實例編號17 : 3-(4-(3·(3-氯-4-異丙氣基苯基）-l，2,4-吟二 唑-5-基）苯基磺醯胺基）丙酸之製備Containing 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4. II. sit-5-yl) benzathine (0.500 g, 1.270 mmol) NaH (0.0 5 6 g '1 · 3 9 6 m) was added to the solution of DMF (3.17 ml). After about 1 min, 3-butyric acid tert-butyl ester (0.233 ml, 1.396 mmol) was added and the reaction mixture was heated to about 6 (TC. After about 48 hours, the reaction mixture was allowed to cool to room temperature and Chromatography on EtOAc (EtOAc/EtOAc) eluted Tetrabutyl 4-butanyl-5-yl)phenylsulfonyldiazepinedipropionate (0.24 g, 29%). LCMS (Table 1, Method c) Rt = 3.43 min, m/ z 667 (M+NH4)+ 〇, to give 3-(4-(3-(3-)-4-isopropoxyphenyl)-1,2,4-oxadiazole as a colorless solid. 3-butyl)phenylsulfonylamino)propionic acid tert-butyl ester (0.28 g, 42%). LCMS (Table 1, Method c) Rt=3.13 min, m/z 521 (M-Η)·〇 Example No. 17 : 3-(4-(3·(3-chloro-4-isopropyloxyphenyl)-l,2,4-oxadiazol-5-yl)phenylsulfonylamino)propionic acid preparation

於含3-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-吟二唑-5·基） 苯基磺醯胺基）丙酸第三丁酯（0·28克，0.536毫莫耳）之二氯 甲烷（6,0毫升）溶液中添加TFA(2.0毫升，26·0毫莫耳）。約3 127788.doc -146- 200840567 小時後’真空濃縮反應混合物且以乙醚使所得固體研散， 經過濾且乾燥，獲得無色固體之3_(4_(3_(3_氣-4-異丙氧基 苯基）-1，2,4_噚二唑-5-基）苯基磺醯胺基）丙酸（〇176克， 70%)。LCMS(表 1，方法c) Rt=2.54 — 466 (M+H)+。 實例編號18 ·· 2,2’-(4-(3-(3ϋ異丙氧基苯基}-1，2,4•嘮二 嗤·5·基）苯基確酿基氮二基）二乙酸之製備3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonylamino)propanoic acid TCA (2.0 mL, 26.0 mmol) was added to a solution of butyl ester (0. 28 g, 0.536 mmol) in dichloromethane (6 mL). After about 3 127788.doc -146-200840567 hours, the reaction mixture was concentrated in vacuo and the obtained solid was triturated with diethyl ether, filtered and dried to give a colorless solid of 3 _(3_(3 _ Phenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonylamino)propanoic acid (〇176 g, 70%). LCMS (Table 1, Method c) Rt = 2.54 - 466 (M + H) +. Example No. 18 ··· 2,2'-(4-(3-(3ϋisopropoxyphenyl}-1,2,4•唠二嗤·5·yl)phenyl-phenyl-diyl) Preparation of acetic acid

將TFA(1.0毫升，12.98毫莫耳）添加於含2,2，_(4_(3_(3备 4-異丙氧基苯基）-1，2,4-吟二唑-5«基）苯基磺醯基氮二基）二 乙酸第三丁醋（0·106克，〇.17〇毫莫耳）之二氯甲烷及 TFA(3.1 9¾升）混合物中。使混合物在周圍溫度下攪拌2小 牯且接著真空》辰縮。所得殘留物以二乙醚研散，經過濾且 乾燥，獲得白色固體之2,2，_(4-(3-(3_氯_4-異丙氧基苯基）_ I2,4-。号二唑基）笨基磺醯基氮二基）二乙酸（63毫克， 〇·122毫莫耳）之白色固體。LCMS(表1，方法c) Rt=1料 min，m/z 508.38 (Μ·Η)· 〇 實例編號19 : 2,2，-(ΜΜ3-氣-4-異丙氧基苯基Μ，2,4_呤二 嗤-5-基）苯基續醯基氮二基）二己酸第三丁醋及2(4七| 氣-4-異丙氧基苯基）el，2,4，二唑_5基）苯基磺醯基）乙酸 第三丁酯之製備 127788.doc -147- 200840567Add TFA (1.0 ml, 12.98 mmol) to 2,2,_(4_(3_(3)4-isopropoxyphenyl)-1,2,4-oxadiazol-5«) Phenylsulfonyldithiodiyl)diacetic acid terpene vinegar (0.106 g, 〇.17 〇 millimol) in a mixture of dichloromethane and TFA (3.193⁄4 liter). The mixture was stirred at ambient temperature for 2 hours and then vacuumed. The residue obtained was triturated with diethyl ether, filtered and dried to give 2,2,-(4-(3-(3-chloro-4-4-isopropoxyphenyl)-I2,4-. A white solid of oxadiazolyl)phenylidenesulfonyldiazepinediacetate (63 mg, 〇122 mmol). LCMS (Table 1, Method c) Rt = 1 min, m/z 508.38 (Μ·Η)·〇 Example No. 19: 2,2,-(ΜΜ3-气-4-isopropoxyphenylhydrazine, 2 , 4_呤二嗤-5-yl)phenyl hydrazinyl diazyl)dihexanoic acid butyl vinegar and 2 (4 -7 | gas-4-isopropoxyphenyl)el, 2, 4, Preparation of tert-butyl oxazol-5(phenyl)sulfonyl)acetate 127788.doc -147- 200840567

在A中將粉末狀K2C〇3(〇 19〇克，ι374毫莫耳）滴加於含 4_(3-(3-氣異丙氧基苯基）-1，2,4-噚二唑-5-基）苯確酿胺 (〇·492克’ 1.249毫莫耳）之無水乙腈（6·25毫升）授拌混合物 中。接著添加2-溴乙酸第三丁酯（0.203毫升，1.374毫莫耳） 且使混合物加熱至8(TC歷時3小時。真空濃縮反應混合物 (懸浮液）且使所得物質研散於DCM中並過濾。濃縮濾液且 經 Analogix系統，使用 RediSep rS 40g管柱，以 0_4〇% EtOAc/庚院之梯度在3〇毫升/分鐘下歷時4〇分鐘直接純 化。合併含產物之溶離份且濃縮。獲得黏性白色固體之 2，2 -(4-(3-(3-氯-4 -異丙氧基苯基）-1，2H二吐-5-基）笨基 石兴&amp;&amp;基氮一基）二乙酸第三丁酷（249毫克，0.400毫莫耳）。 LCMS(表 1，方法c) Rt=3.i7 min，m/z 639 (M+NH4)+，及白 色固體之2-(4-(3-(3-氯-4-異丙氧基苯基）-i，2,4-嘮二唑_5-基）苯基磺醯基）乙酸第三丁酯（121毫克，〇·238毫莫耳）。 LCMS(表 1 ’ 方法c) Rt=2.81 min，m/z 508 (Μ+Η)+ 〇 實例編號20 ·· 2-(4-(3-(3-氣·4-異丙氧基苯基）-ΐ，2,4-吟二 唑-5-基）苯基磺醯胺基）乙酸之製備Powdered K2C〇3 (〇19〇g, ι374 mmol) was added dropwise to A-containing 4-(3-(3-isopropoxyphenyl)-1,2,4-oxadiazole- 5-Alkyl) Benzylamine (〇·492 g ' 1.249 mmol) of anhydrous acetonitrile (6·25 mL) was added to the mixture. Next, 2-bromoacetic acid tert-butyl ester (0.203 ml, 1.374 mmol) was added and the mixture was heated to 8 (TC) for 3 hours. The reaction mixture was concentrated in vacuo (the suspension) and the material was applied to DCM and filtered. The filtrate was concentrated and directly purified by an Analogix system using a RediSep rS 40 g column, eluting with a gradient of 0 to 4% EtOAc/g. 2,2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2H dioxa-5-yl) stupyl sylvestre &amp;&amp; Diacetic acid tert-butyl (249 mg, 0.400 mmol) LCMS (Table 1, Method c) Rt = 3.i7 min, m/z 639 (M+NH4)+, and white solid 2- 4-(3-(3-chloro-4-isopropoxyphenyl)-i,2,4-oxadiazole-5-yl)phenylsulfonyl)acetic acid tert-butyl ester (121 mg, hydrazine) · 238 millimoles. LCMS (Table 1 'Method c) Rt=2.81 min, m/z 508 (Μ+Η)+ 〇Example No. 20 ·· 2-(4-(3-(3-气·4 Preparation of -isopropoxyphenyl)-indole, 2,4-oxadiazol-5-yl)phenylsulfonylamino)acetic acid

在乂中將TFA(2.0毫升，26.0毫莫耳）滴加於含2-(4-(3-(3一 氯-4-異丙氧基苯基）·1，2,4-吟二唑-5-基）苯基磺醯胺基）乙 127788.doc -148- 200840567 酸第三丁酯（0·121克，0.238毫莫耳）tDCM(5〇毫升）攪拌 混合物中。使混合物在周圍溫度下攪拌3小時，接著真空 濃縮。所得固體以乙醚研散，經過濾且乾燥，獲得白色固 體之2-(4-(3-(3-氯-4-異丙氧基苯基卜丨，2,4-喝二唑巧_基）苯 基磺酸胺基）乙酸（46毫克，〇·ΐ〇2毫莫耳）。LCMS(表1，方 法 c) Rt=2.14 min，m/z 450.34 (M-Η)-。 實例編號21 : 2-(5-(3-(3-氣_4·異丙氧基苯基}-1，2,4_号二 唑基）-3,4-二氫異喹啉-2(1Η)-基）乙酸第三丁酯之製備TFA (2.0 ml, 26.0 mmol) was added dropwise to the solution containing 2-(4-(3-(3-chloro-4-isopropoxyphenyl)·1,2,4-oxadiazole) -5-yl)phenylsulfonylamino)ethyl 127788.doc -148- 200840567 Acidic tert-butyl ester (0. 121 g, 0.238 mmol) tDCM (5 mL) was stirred in the mixture. The mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The obtained solid was triturated with diethyl ether, filtered and dried to give 2-(4-(3-chloro-4-isopropoxyphenyl), 2,4-dioxazole. Phenyl sulfonate amino) acetic acid (46 mg, 〇·ΐ〇 2 mmol) LCMS (Table 1, Method c) Rt = 2.14 min, m/z 450.34 (M-Η)-. Example No. 21 : 2-(5-(3-(3-Gas_4.isopropoxyphenyl}-1,2,4-oxadiazolyl)-3,4-dihydroisoquinoline-2 (1Η) -base) Preparation of tert-butyl acetate

〇 於含3-(3-氯-4-異丙氧基苯基）-5-(1，2,3,4-四氫異喹啉巧-基）-1，2,4-口号二吐（0.0726 克，0.196毫莫耳）之 DMF(1.963 毫 升）溶液中添加K2C03(0.054克，0·393毫莫耳），接著添加 溴乙酸第三丁酯（0.030毫升，0.206毫莫耳）。約48小時 後，過慮反應混合物，經真空濃縮且進行層析純化，獲得 無色油之2-(5-(3-(3-氯-4-異丙氧基苯基）-1，2,4-嘮二唑-5-基）-3,4-二氫異喹啉-2(1H)-基）乙酸第三丁酯，該油於靜置 後固化。LCMS(表 1，方法 c) Rt=3.41 min，m/z 486 (M+H)+。 實例編號22 : 5-(3-(3-氯-4-異丙氧基苯基）-l，2,4-噚二唑-5-基）-3,4-二氫異喹啉-2(1H)-甲酸第三丁酯之製備 127788.doc -149- 200840567〇 containing 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolinyl-yl)-1,2,4- s. K2C03 (0.054 g, 0. 393 mmol) was added to a solution of (0.0726 g, 0.196 mmol) in DMF (1.963 mL), followed by butyl bromoacetate (0.030 mL, 0.206 mmol). After about 48 hours, the reaction mixture was taken up in vacuo tolulululululululululululululululululululululu - oxadiazole-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid tert-butyl ester, which solidified upon standing. LCMS (Table 1, Method c) Rt = 3.41 min, m/z 486 (M+H)+. Example No. 22: 5-(3-(3-Chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinoline-2 Preparation of (1H)-T-butyl formate 127788.doc -149- 200840567

於含2-(第三丁氧基羰基）-：i，2,3,4-四氫異喹啉-5-甲酸 (0.380克，1·371毫莫耳）之DMF(1662毫升）漿料中添加 EDC(0.263克，1.371毫莫耳）接著添加HOBT鹽酸鹽。約}DMF (1662 ml) slurry containing 2-(t-butoxycarbonyl)-:i,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (0.380 g, 1.371 mmol) EDC (0.263 g, 1.371 mmol) was added followed by HOBT hydrochloride. approximately}

小時後，添加含〇3_氣-&gt;^’-羥基-4-異丙氧基苯甲脒（0.285 克，1.246毫莫耳）之DMF(〇.83l毫升）溶液，且使反應混合 物加熱至140°C歷時約1小時。真空濃縮反應混合物且在矽 膠上進行層析純化，獲得5-(3-(3-氯-4-異丙氧基苯基）-1，2,4-’一嗤-5-基）-3,4_二氫異喧琳_2(ih)_甲酸第三丁酯 (0.403 克 ’ 69%)之無色油。LCMS(表 1，方法 c) Rt=3.43 min，m/z 471 (M+H)+。 實例編號23 : 3_(3-氣·4-異丙氧基苯基卜5_(i，2,3,4-四氫異 嗟琳基）-1，2,4-吟二嗤之製備After an hour, a solution of DM3_gas-&gt;^'-hydroxy-4-isopropoxybenzhydrazide (0.285 g, 1.246 mmol) in DMF (〇.83 ml) was added and the reaction mixture was heated. It takes about 1 hour to reach 140 °C. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel to afford 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-'-indol-5-yl)-3 , 4_Dihydroisoindolene_2 (ih)-tert-butyl formate (0.403 g '69%) of a colorless oil. LCMS (Table 1, Method c) Rt = 3.43 min, m/z 471 (M+H)+. Example No. 23: Preparation of 3-(3-gas·4-isopropoxyphenyl b-5-(i,2,3,4-tetrahydroisoindolyl)-1,2,4-anthracene

於含5-(3-(3-氯-4-異丙氧基苯基^，厶‘崎二唑-5-基）_ 3,4_二氩異喹啉-2(1H)-曱酸第三丁酯（〇4〇3克，〇·858毫莫 耳）之二气烧（17.15毫升）溶液中添加含4 ν HC1之二哼烷溶 、夜（3 · 86毛升’ 1 5 ·44宅莫耳）。約1 5小時後，過濾、反應混合 物。使所得固體分溶於EtOAc及飽和NaHC〇d。分離有機 127788.doc -150- 200840567 層，經脫水（MgS04)、過濾且真空濃縮，獲得無色固體之 3-(3-氯-4-異丙氧基苯基）-5-(1，2,3,4-四氫異喹啉-5-基）· 1，2,4-噚二唑（0.230 克，73%)。LCMS(表 1，方法c) Rt=2.00 min，w/z 372 (M+H)+。 實例編號24 : 2·(5-(3-(3-氯-4-異丙氧基苯基）-1，2,4·噚二 嗤_5_基）_3,4-二氫異喹啉-2(1Η)-基）乙酸之製備Containing 5-(3-(3-chloro-4-isopropoxyphenyl), oxime-soxadiazol-5-yl)-3,4-diarisoquinoline-2(1H)-decanoic acid A solution of the third butyl ester (〇4〇3 g, 〇·858 mmol) in a gas-fired (17.15 ml) solution containing 4 ν HC1 in dioxane, night (3 · 86 hair liters ' 1 5 · After a period of about 15 hours, the mixture was filtered and the residue was dissolved in EtOAc and sat. NaHC EtOAc. 127 </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Concentration to give 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)·1,2,4 as a colorless solid - oxadiazole (0.230 g, 73%). LCMS (Table 1, Method c) Rt = 2.00 min, w/z 372 (M+H) +. Example No. 24: 2·(5-(3-(3) -Chloro-4-isopropoxyphenyl)-1,2,4·indenyl-5_yl)_3,4-dihydroisoquinolin-2(1Η)-yl)acetic acid

於含2-(5-(3-(3-氯-4-異丙氧基苯基）4,2,4-吟二唑-5-基）· 3,4-二氫異喹啉-2(1H)-基）乙酸第三丁酯（〇1319克，〇·273 t莫耳）之二氯甲烷（10毫升）溶液中添加三異丙基矽烷 (0·056笔升，0.273宅莫耳），接著添加TFA(2毫升）。約15Containing 2-(5-(3-(3-chloro-4-isopropoxyphenyl)4,2,4-oxadiazol-5-yl)·3,4-dihydroisoquinoline-2 (1H)-yl)acetic acid tert-butyl ester (〇1319 g, 273·273 tmol) in dichloromethane (10 ml) was added with triisopropyl decane (0·056 liters, 0.273 house moles) ), then TFA (2 mL) was added. About 15

小柃後，真空》辰縮反應混合物。所得固體以乙醚研散，經 過濾及乾燥，獲得灰白色固體之2_(5_(3_(3-氯_4_異丙氧基 苯基一唑-5-基）-3,4-二氫異喹啉_2(1Η&gt;基）乙酸 (0.138克，93%)。LCMS(表 1，方法c) Rt=2 〇〇 _，428 (M+H)+ 〇 實例編號25 ·· 3·(5_(3·(3_氣_4·異丙氧基苯基崎二 峻_5_基）-3,4-二氫異啥琳·2(1Η)•基）丙酸第三丁酯之製備After the small crucible, the vacuum "shrinks the reaction mixture. The obtained solid was triturated with diethyl ether, filtered and dried to give 2-(5-(3-(3-chloro-4-isopropoxyphenyl-azol-5-yl)-3,4-dihydroisoquine as an off-white solid. Porphyrin-2 (1Η&gt;) acetic acid (0.138 g, 93%). LCMS (Table 1, Method c) Rt = 2 〇〇 _, 428 (M+H) + 〇 Example No. 25 ·· 3·(5_( 3·(3_气_4·isopropoxyphenyl succinyl _5_yl)-3,4-dihydroisoindolyl·2(1Η)•yl) Preparation of tert-butyl propionate

127788.doc -151 - 200840567 於έ 3_(3-氯-4 -異丙氧基苯基）-5·(1，2,3,4-四氫異啥琳j 基）-l，2,4-今二嗤（0·1088克，〇·294毫莫耳）之叫^(2 94毫 升）（簡單加熱至4CTC使之完全溶解）中添加K2c〇3(〇e()81 克’ 0.588毫莫耳）及3-溴丙酸第三丁酯（〇.〇46毫升，〇 276 毫莫耳）且使混合物在周圍溫度下攪拌2小時。添加額外之 3-溴丙酸第三丁酯（0·053毫升，〇·315毫莫耳）且使反應在 60 C下攪拌隔一週末。添加額外之％溴丙酸第三丁酯 (0.053毫升，〇·315毫莫耳）且使反應混合物在6〇〇c下加熱隔 籲 夜。添加額外之Κπ〇3(0·041克，0.294毫莫耳），接著添加 3-溴丙酸第三丁酯（0·053毫升，0·315毫莫耳）。使反應在 60°C下加熱隔夜。反應混合物經過慮且真空濃縮濾液，獲 得約179毫克之粗製黃色油。使該粗製殘留物經Anal〇gix 系統，使用RediSep RS 12 g管柱，以0-45% EtOAc/庚烧之 梯度在15毫升/分鐘下歷時35分鐘純化。合併第23_28溶離 份並經濃縮，獲得淡黃色油之3-(5-(3-(3-氯-4-異丙氧基苯 基）-1，2,4^号二唑_5_基）_3,4_二氫異喹啉基）丙酸第三 ⑩ 丁酯（91毫克，0.183毫莫耳）。LCMS(表1，方法c) Rt=3.39 min，m/z 500·72 (M+H)+。 實例編號26 : 3-(5-(3-(3-氣-4-異丙氧基苯基）-l，2,4-嘮二 吐基）·3,4-二氫異喹啉-2(1H)-基）丙酸，TFA鹽之製備127788.doc -151 - 200840567 έ 3_(3-Chloro-4-isopropoxyphenyl)-5·(1,2,3,4-tetrahydroisoindolyl j-)-l,2,4 - Today's two 嗤 (0·1088 g, 〇 · 294 millimoles) is called ^ (2 94 ml) (simple heating to 4 CTC to completely dissolve) K2c 〇 3 (〇e () 81 g ' 0.588 毫Mohr) and tert-butyl 3-bromopropionate (〇.〇46 ml, 〇276 mmol) and the mixture was stirred at ambient temperature for 2 hours. Additional tributyl 3-bromopropionate (0. 053 mL, 〇 315 mmol) was added and the reaction was stirred at 60 C overnight. Additional % tributyl bromopropionate (0.053 ml, 〇 315 mmol) was added and the reaction mixture was heated at 6 ° C overnight. Additional Κπ〇3 (0·041 g, 0.294 mmol) was added followed by tert-butyl 3-bromopropionate (0·053 mL, 0·315 mmol). The reaction was allowed to heat overnight at 60 °C. The reaction mixture was concentrated and the filtrate was concentrated in vacuo to yield 179 mg of crude crude oil. The crude residue was purified on a EtOAc EtOAc EtOAc EtOAc. The 23_28 fractions were combined and concentrated to give 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4^diazole _5-yl) as a pale yellow oil. _3,4_Dihydroisoquinolinyl)propionic acid third 10 butyl ester (91 mg, 0.183 mmol). LCMS (Table 1, Method c) Rt = 3.39 min, m/z 500·72 (M+H)+. Example No. 26: 3-(5-(3-(3-Ga-4-isopropoxyphenyl)-l,2,4-indolyl)-3,4-dihydroisoquinoline-2 Preparation of (1H)-yl)propionic acid, TFA salt

127788.doc -152- 200840567 於含3-(5-(3-(3-氯-4_異丙氧基苯基}-1，2，‘哼二唑·5_基&gt; 3,4-一氫異喹啉-2(1H)-基）丙酸第三丁酯（〇〇91克，〇183亳 莫耳）之二氣曱烷（6·0毫升）中添加TFA(1.5毫升）且使混合物 在周圍溫度下攪拌隔夜。真空濃縮反應混合物，且使所得 粗製產物洛於小i DCM中。添加乙_直到沉殿出固體為 止。過濾混合物，以乙醚洗滌且乾燥，獲得淡黃色固體之 3-(5-(3-(3-氣-4-異丙氧基苯基卜^，‘嘮二唑乃_基）_3,4•二 氫異喹啉-2(1H)-基）丙酸，TFA鹽（74·7毫克，〇134毫莫 耳）[CMS(表 1 ，方法 c) 〇4 min， m/z 442.25 (M+H)+。4 NMR (4⑽ MHz，DMSO) δ ppm 8.18-8,11 (dd， J=2.07 6.76 Hz5 1H)? 8.11-8.06 (d, J=2.01 Hz? 1H), 8.06-7.99 (J=2.02? 8.64 Hz, 1H)5 7.61-7.53 (J=6.58, 6,58 Hz， 1Η)，7·45-7·37(】=8·8Ηζ，1Η)，4·90-4·78(ιη，1Η)，4·65-4.46 (s，2H)，3·71-3·51 (s，3H)，3.51-3.38 (J=6.87, 6·87 Hz， 3Η)，2·91-2·81 (t，J = 7.32，7·32 Hz，2H)及 1.39-1.33 (d， 6H)。 製備例編號7· 4 -異丙氧基_3_(三氟甲基）节猜127788.doc -152- 200840567 Containing 3-(5-(3-(3-chloro-4_isopropoxyphenyl}-1,2,'oxadiazole·5-yl] 3,4- TCA (1.5 ml) was added to the dihydrogen isobutyroline-2(1H)-yl)propionic acid tert-butyl ester (〇〇91 g, 〇183 亳mol) in dioxane (6.0 mL). The mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo and the obtained crude product was taken from a small i DCM. 3-(5-(3-(3-Gas-4-isopropoxyphenyl), 'oxadiazole-yl}-3,4•Dihydroisoquinolin-2(1H)-yl)- Acid, TFA salt (74·7 mg, 〇134 mmol) [CMS (Table 1, Method c) 〇 4 min, m/z 442.25 (M+H)+. 4 NMR (4 (10) MHz, DMSO) δ ppm 8.18-8,11 (dd, J=2.07 6.76 Hz5 1H)? 8.11-8.06 (d, J=2.01 Hz? 1H), 8.06-7.99 (J=2.02? 8.64 Hz, 1H)5 7.61-7.53 (J= 6.58, 6,58 Hz, 1Η),7·45-7·37(]=8·8Ηζ,1Η),4·90-4·78(ιη,1Η),4·65-4.46 (s,2H) ,3·71-3·51 (s,3H), 3.51-3.38 (J=6.87, 6·87 Hz, 3Η), 2 91-2 · 81 (t, J = 7.32,7 · 32 Hz, 2H) and 1.39-1.33 (d, 6H) Preparation Example No. 7.4 - isopropoxy _3_ (trifluoromethyl) Section guess

在氮氣中使含4-羥基-3-(三氟甲基）苄腈（5·89克，31·5毫 莫耳）及二笨基膦（13.21克，50.4毫莫耳）之無水THF(200毫 升）混合物在周圍溫度下攪拌5分鐘，於溶液中添加dbad (11.60克，50.4¾莫耳），攪拌5分鐘後，添加2•丙醇（3〇3 127788.doc -153- 200840567 毫升，39·3毫莫耳）。使混合物在周圍溫度下攪拌72小時。 減壓移除溶劑。所得油以〇-60°C石油/醚（2〇〇毫升）研散， 系二過/慮移除乳化膦且使粗製產物經石夕膠以庚烧/乙酸乙酉旨 (4:1)溶離進一步純化。使單離之油溶於二氯甲烷（2〇〇毫 升）中且在周圍溫度下與TFA(4.85毫升，63·〇毫莫耳）授掉 90分鐘。以2·5 N Na〇H(30毫升）使溶液鹼化且使產物分溶 於DCM及鹼性水溶液相中，獲得粗製之4_異丙氧基_3 •(三 氟曱基）苄腈（6.56毫克，91%)。LCMS(表1，方法a)4-Hydroxy-3-(trifluoromethyl)benzonitrile (5·89 g, 31·5 mmol) and diphenylphosphine (13.21 g, 50.4 mmol) in anhydrous THF (under nitrogen) 200 ml) The mixture was stirred at ambient temperature for 5 minutes, dbad (11.60 g, 50.43⁄4 mol) was added to the solution, and after stirring for 5 minutes, 2·propanol (3〇3 127788.doc -153-200840567 ml, 39·3 millimoles). The mixture was stirred at ambient temperature for 72 hours. The solvent was removed under reduced pressure. The oil obtained was ground at 〇-60 ° C petroleum/ether (2 〇〇 ml), and the emulsified phosphine was removed and the crude product was dissolved in the sulphuric acid/glycolate (4:1). Further purification. The isolated oil was dissolved in dichloromethane (2 Torr) and allowed to react with TFA (4.85 mL, 63·Mm) at ambient temperature for 90 minutes. The solution was basified with 2·5 N Na〇H (30 mL) and the product was partitioned between DCM and basic aqueous phase to afford crude 4-isopropoxy-3 •(trifluoromethyl)benzonitrile (6.56 mg, 91%). LCMS (Table 1, Method a)

Rt=2.32 min，1H NMR (400 MHz，CDC13) δ 7.85(d，1H)， 7.75(dd，1H)，7·06 (d，1H)，4.73 (m，1H)，1.41 (dd，6H)。 製備例編號8 : (Z)-Ν’-幾基-4-異丙氧基- 3-(三氟甲基）苯 曱脒Rt=2.32 min,1H NMR (400 MHz, CDC13) δ 7.85 (d, 1H), 7.75 (dd, 1H), 7.06 (d, 1H), 4.73 (m, 1H), 1.41 (dd, 6H) . Preparation No. 8: (Z)-Ν'-Methoxy-4-isopropoxy-3-(trifluoromethyl)benzene hydrazine

在氮氣中，使4-異丙氧基-3-(三氟甲基）苄腈（6·5克， 28.4¾莫耳）及50 %經基胺水溶液（5·21毫升，85毫莫耳）之 EtOH(20.0毫升）在60°C下加熱18小時。真空移除溶劑且使 殘留物與MeOH共沸。使殘留固體藉由自乙酸乙酯/3〇_6〇 〇C石油/醚混合物（1:2)沉澱純化，獲得（z)-n，-羥基-4-異丙 氧基-3-(三氟曱基）苯甲脒（2.51克，33.8%)。LCMS(表1， 方法 b) Rt=1.89 min，m/z 263.13 (M+H)+。 製備例編號9 ·· (S)-3-氣-4-(四氫呋喃-3-基氧基）苄腈 127788.doc -154- 2008405674-isopropoxy-3-(trifluoromethyl)benzonitrile (6.5 g, 28.43⁄4 mol) and 50% aqueous solution of the base amine (5·21 ml, 85 mmol) under nitrogen. EtOH (20.0 mL) was heated at 60 ° C for 18 hours. The solvent was removed in vacuo and the residue was azeotroped with MeOH. The residual solid was purified by precipitation from ethyl acetate/3〇_6〇〇C petroleum/ether mixture (1:2) to obtain (z)-n,-hydroxy-4-isopropoxy-3-(three Fluorinyl) benzamidine (2.51 g, 33.8%). LCMS (Table 1, Method b) Rt = 1.89 min, m/z 263.13 (M+H)+. Preparation No. 9 ··(S)-3-Gas-4-(tetrahydrofuran-3-yloxy)benzonitrile 127788.doc -154- 200840567

在氮氣中，使含3-氯-4-羥基苄腈（8·7〇克，56·7毫莫耳） 及一笨基膦（23.77克，91毫莫耳）之無水THF(218毫升）混合 物在周圍溫度下攪拌5分鐘。於溶液中添加DBAD(20.87 克 I莫耳）’擾拌5分鐘後，添加含（S)-(+)-3-經基四氫 夫南（3.87¾升，56.7毫莫耳）之THF(1〇毫升）。使混合物在 • ㊄圍溫度下攪拌24小時，減壓移除溶劑。使殘留物溶於二 氯甲烷（200毫升）中且與TFA(2182毫升，283毫莫耳）攪 拌。以氫氧化鈉水溶液使溶液鹼化且使產物分溶於DcM及 鹼性水溶液相中。DCM以硫酸鎂脫水，經過濾且減壓移除 溶劑，獲得油狀物。使該油與〇 —6〇r石油/醚（2〇〇毫升）攪 伴，經冷卻且過慮。減壓移除溶劑，獲得粗製〇3_氯_4_ (四氫呋喃-3-基氧基）苄腈（ιι·2克）。Rt 2 〇6 min，m/z 378 2 (M+H)+。 馨 製備例編號W · (S，Z)-3 -氣_N’_經基_4_(四氫咬味基氧 基）苯甲脒3-Chloro-4-hydroxybenzonitrile (8·7 g, 56·7 mmol) and a stupylphosphine (23.77 g, 91 mmol) in anhydrous THF (218 mL) The mixture was stirred at ambient temperature for 5 minutes. After adding DBAD (20.87 g I mole) to the solution for 5 minutes, add (S)-(+)-3-trans-tetrahydrofuran (3.873⁄4 liter, 56.7 mmol) of THF ( 1 〇 ml). The mixture was stirred at a temperature of 24 hours for 24 hours, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and EtOAc (EtOAc) The solution was basified with an aqueous solution of sodium hydroxide and the product was dissolved in a mixture of DcM and basic aqueous phases. The DCM was dried over magnesium sulfate, filtered and solvent was evaporated under reduced pressure to give an oil. The oil was stirred with 〇-6〇r petroleum/ether (2 〇〇 ml), cooled and passed through. The solvent was removed under reduced pressure to give crude EtOAc (EtOAc) (EtOAc). Rt 2 〇 6 min, m/z 378 2 (M+H)+.馨 Preparation Example No. W · (S, Z) - 3 - gas _N'_ carbyl _4_(tetrahydrobitiyloxy) benzamidine

在氮氣中，使（S)-3-氣-4-(四氫吱喃基氧基)苄腈（ιι·2 克’ 5 0 · 1毫莫耳）及50%經基胺水溶液（3 3 1克，5 0· 1毫莫 耳）之EtOH(150.0毫升）在6(TC下攪拌18小時。真空移除溶 127788.doc -155- 200840567 劑且使殘留物與MeOH共沸。使殘留固體自乙酸乙酯/30-60 C石油/鱗混合物（1:2)沉殿純化’獲得（S，Z)-3 -氣-N’ -輕 基四氫呋喃-3-基氧基）苯甲脒（5.3克）。LCMS(表1，方 法 b) Rt=l,52 min，m/z 257.09 (M+H)+。 製備例編號11 : 4_嗎啉基_3-(三氟甲基）苄腈(S)-3-Ga-4-(tetrahydrofurfuryloxy)benzonitrile (ιι·2 g '5 0 · 1 mmol) and 50% aqueous solution of the base amine (3 3 ) 1 g, 5 0 1 1 mmol of EtOH (150.0 ml) was stirred at 6 (TC) for 18 hours. The solution was dissolved in vacuo to dissolve 127788.doc-155-200840567 and the residue was azeotroped with MeOH. Purification from ethyl acetate/30-60 C petroleum/scale mixture (1:2) to obtain (S,Z)-3- gas-N'-light tetrahydrofuran-3-yloxy)benzimidazole 5.3 grams). LCMS (Table 1, Method b) Rt = 1 , 52 min, m/z 257.09 (M+H)+. Preparation No. 11 : 4_morpholinyl-3-(trifluoromethyl)benzonitrile

於含4-氟-3-(三氟甲基）苄腈（15克，79毫莫耳）之二甲基 亞砜（160毫升）溶液中添加嗎啉（丨3.8毫升，159毫莫耳）及 碳酸鉀（16.4克，119毫莫耳）。使混合物在約9〇°C加熱18小 時。使混合物冷卻至周圍溫度且過濾移除固體。使濾液分 溶於乙酸乙_(1·8升）及水（ι·5升）中。有機層以水（ι·〇升）及 鹽水（1.0升）洗滌且以無水硫酸鎂脫水。真空移除溶劑，獲 得4-嗎琳基-3-(三氟曱基）苄腈（17·25克，85〇/〇)。NMR (DMSO-4 400 MHz) δ 8.18 (d，J=2.05 Ηζ，1Η)，8.09 (dd， J=8.51，2·06 Hz, 1H)，7·6〇 (d，J=8.52 Hz，1H)，3.69-3.75 (m，4H)，2.97-3.04 (m，4H)。 製備例編號12 : N，_羥基·4_嗎啉基_3气三氟甲基）苯甲脒Add morpholine (丨3.8 ml, 159 mmol) to a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (15 g, 79 mmol) in dimethyl sulfoxide (160 mL) And potassium carbonate (16.4 g, 119 mmol). The mixture was heated at about 9 ° C for 18 hours. The mixture was allowed to cool to ambient temperature and filtered to remove solids. The filtrate was dissolved in ethyl acetate (1·8 liters) and water (1·5 liters). The organic layer was washed with water (1 mL) and brine (1.0 L) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give 4-y-n-yl-3-(trifluoromethyl)benzonitrile (17·25 g, 85 〇 / 。). NMR (DMSO-4 400 MHz) δ 8.18 (d, J = 2.05 Ηζ, 1 Η), 8.09 (dd, J = 8.51, 2·06 Hz, 1H), 7·6 〇 (d, J = 8.52 Hz, 1H) ), 3.69-3.75 (m, 4H), 2.97-3.04 (m, 4H). Preparation No. 12: N, _hydroxy·4_morpholinyl-3-trifluoromethyl)benzamide

於含4-嗎啉基-3-(三氟甲基）苄腈（17·3克，67·3毫莫耳）之 127788.doc * 156 - 200840567 乙醇（400毫升）溶液中滴加50%羥基胺水溶液（4.9毫升， 74.1毫莫耳）。使混合物在約65°C下加熱24小時。使混合物 冷卻至周圍溫度且過濾移除固體。使濾液分溶於乙酸乙酯 (1.8升）及水（1.5升）中。有機層以水（1·〇升）及鹽水（ι·〇升）洗 滌且以無水硫酸鎂脫水。真空移除溶劑，獲得N，-羥基-4-嗎琳基- 3-(三氟甲基）苄腈（18.6克，91%)之順式/反式異構 物之混合物。LCMS(表 1，方法b) Rt=1.85 min，m/z 290.15 (M+H)+; ln NMR (DMSO-i/6, 400 MHz) 9.75 (s? 1H), 8.09-8.16(m，lH)，7.89-7.96 (m，lH)，7.52-7.58 (m，lH)，3.66-3.72 (m，4H)，2.83-2.93 (m，4H)。 製備例編號13 : 5_甲氧基二氫-2H-吡嗪-1-甲酸节酯Add 50% to a solution containing 127 ku. An aqueous solution of hydroxylamine (4.9 ml, 74.1 mmol). The mixture was heated at about 65 ° C for 24 hours. The mixture was allowed to cool to ambient temperature and filtered to remove solids. The filtrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1·m) and brine (1·m) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give a mixture of &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&& LCMS (Table 1, Method b) Rt = 1.85 min, m/z 290.15 (M+H)+; ln NMR (DMSO-i/6, 400 MHz) 9.75 (s? 1H), 8.09-8.16 (m, lH ), 7.89-7.96 (m, lH), 7.52-7.58 (m, lH), 3.66-3.72 (m, 4H), 2.83-2.93 (m, 4H). Preparation No. 13 : 5_Methoxydihydro-2H-pyrazine-1-carboxylic acid ester

使含3-側氧基哌嗪-1-曱酸苄酯（2.50克，10.67毫莫耳）之 CH2C12(100毫升）溶液冷卻至〇°c，且以Na2CO3(23.0克， 217¾莫耳）處理10分鐘。一次添加純的三甲基氧鑌四氟删 酸鹽（5.50克，37·2毫莫耳），接著使反應升溫至室溫歷時6 小時。將反應倒入水（100毫升）中且分層。水層以50毫升 CHWl2再萃取並以鹽水（1〇〇毫升）洗滌合併之有機層。有機 層以硫酸鈉脫水，經過濾及濃縮，獲得5_甲氧基_3,6_二 氫-2H-吡嗪-1-甲酸苄酯（2.51克，95%)之油。LCMS(表1， 方法 a) Rt=3.00 min，m/z 249.24 (M+H)+，； 4 NMR (400 MHz，DMSO-d6) δ 7.36 (m，5H)，5·16 (s，2H)，3·96 (s，2H)， 127788.doc -157- 200840567 3.68(S，3H)，3.54(s，2H)，3.47(m，2H)。 -a]吡嗪 製備例編號14 : 甲基·5,6·二氫-8H·咪唾并Q 2 甲酸苄酯 1’A solution of 3-benzyloxypiperazine-1-indole benzyl ester (2.50 g, 10.67 mmol) in CH2C12 (100 mL) was cooled to &lt;RTI ID=0.0&gt;&gt; 10 minutes. Pure trimethyloxonium tetrafluorodecarboxylate (5.50 g, 37.2 mmol) was added in one portion, then the reaction was allowed to warm to room temperature for 6 hours. The reaction was poured into water (100 mL) and layered. The aqueous layer was re-extracted with 50 mL of CH.sub.2 and washed with brine (1 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give ethyl <RTI ID=0.0>#</RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; LCMS (Table 1, Method a) Rt = 3.00 min, m/z 249.24 (M+H)+,; 4 NMR (400 MHz, DMSO-d6) δ 7.36 (m, 5H), 5·16 (s, 2H) ), 3·96 (s, 2H), 127788.doc -157- 200840567 3.68 (S, 3H), 3.54 (s, 2H), 3.47 (m, 2H). -a]pyrazine Preparation No. 14 : methyl·5,6·dihydro-8H·imido and Q 2 benzyl formate 1’

在『:下於含3_甲氧基'…二氫吼嗪_丄叫甲酸酯(4輔 關^宅莫，kMe〇H(2〇〇毫升）溶液中添加块丙基胺 ,、 〇 90 I莫耳）。使混合物回流加熱5小時，接著冷 部至至溫且濃縮。使殘留物溶於} N Hci〇⑻毫升）中且以 3x75笔升乙酸乙酯洗滌。水溶液以固體中和並以 2x100毫升乙酸乙酯萃取。合併之萃取液以1〇〇毫升飽和 NaCl溶液洗滌，經過濾且濃縮。以乙醚使殘留物研散，經 過濾且減壓乾燥，獲得灰白色固體之3-甲基_5，卜二氫_811_ 咪嗤并[l，2-a]吡嗪-7·甲酸苄酯（2.91克，60%)。LCMS(表 1，方法a) Rt=3.07 min，m/z 272.11 (M+H)+_; 4 NMR (400 MHz，DMSO-d6) δ 7·30 (m，5H)，6.58 (q，1H)，5·13 (s，2H)， 4·55 (s，broad, 2H)，3·84 (s，4H)，2·10 (s，3H)。 製備例編號l5 ·· 蛾甲基·5,6-二氫-8H-咪嗤并丨l，2-a]nb 嗪-7-甲酸苄酯Add propylamine, 〇 in a solution containing 3_methoxy '... dihydropyridazine _ 丄 called formate (4 关 ^ ^ house Mo, kMe 〇 H (2 〇〇 ml) 90 I Mo). The mixture was heated under reflux for 5 hours, then cooled to warmness and concentrated. The residue was dissolved in EtOAc (EtOAc) (EtOAc) The aqueous solution was neutralized with a solid and extracted with 2×100 mL ethyl acetate. The combined extracts were washed with 1 mL of a saturated NaCl solution, filtered and concentrated. The residue was triturated with diethyl ether, filtered and dried under reduced pressure to give 3-methyl <RTIgt;5,</RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 2.91 grams, 60%). </ RTI> <RTIgt ), 5·13 (s, 2H), 4·55 (s, broad, 2H), 3.84 (s, 4H), 2·10 (s, 3H). Preparation No. l5 ·· Moth methyl·5,6-dihydro-8H-imidazolium l,2-a]nbazine-7-formic acid benzyl ester

127788.doc -158- 200840567 於含3-甲基-5,6-二氫咪唑并[1，2-糾吼嗪_7(811)-甲酸苄酯 (1·085克’ 4.00毫莫耳^之匕^二氯乙烷（60毫升）溶液中添加 NIS(4.50克，20.00毫莫耳）並使反應回流加熱一小時。使 反應冷卻至室溫且倒入100毫升飽和之5%硫代硫酸鈉溶液 中。使層分離且以1，2-二氯乙烷（40毫升）再萃取水層。合 併之有機層以水（100毫升）洗滌，以硫酸鈉脫水，經過濾且 濃縮。藉以3x50毫升之乙醚研散自殘留物萃取產物。過濾 萃取液且濃縮，獲得淺黃色油之2-碘-3-曱基-5,6-二氫-8H-咪唑并[l，2-a]吡嗪-7-甲酸苄酯（1·42克，89%)。LCMS(表 1，方法a) Rt=3.32 min，m/z 398,59 (M+H)+-; !H NMR (400 MHz，CHC13) δ 7.35 (m，5H)，5.13 (s，2H)，4·56 (s，寬峰， 2H)，4·38 (t，2H)，3.82 (s，寬峰，2H)，2·09 (s，3H)。 製備例編號l6 : 3_甲基·5,6_二氫-8H_咪峻并[l，2-a]吼嗓-2,7-二甲酸7-苄酯127788.doc -158- 200840567 Containing 3-methyl-5,6-dihydroimidazo[1,2- oxazine-7 (811)-benzyl benzoate (1·085 g ' 4.00 mmol) NIS (4.50 g, 20.00 mmol) was added to a solution of dichloroethane (60 ml) and the reaction was heated at reflux for one hour. The reaction was cooled to room temperature and poured into 100 ml of saturated 5% thiosulfuric acid. The organic layer was washed with water (100 ml), dried over sodium sulfate, filtered and concentrated. The ether of ML was spun from the residue to extract the product. The extract was filtered and concentrated to give 2-iodo-3-mercapto-5,6-dihydro-8H-imidazo[1,2-a]pyr. Benzene-7-formic acid benzyl ester (1. 42 g, 89%). LCMS (Table 1, Method a) Rt = 3.32 min, m/z 398, 59 (M+H) + -; !H NMR (400 MHz , CHC13) δ 7.35 (m, 5H), 5.13 (s, 2H), 4·56 (s, broad peak, 2H), 4·38 (t, 2H), 3.82 (s, broad peak, 2H), 2 ·09 (s, 3H). Preparation No. l6: 3_Methyl·5,6-dihydro-8H_mithio[l,2-a]indole-2,7-dicarboxylic acid 7-benzyl ester

使含2-碘-3-甲基-5,6-二氫咪唑并[i，2-a]吡嗪-7(8H)-曱酸 苄酯（900毫克，2.266毫莫耳）之無水THF(25毫升）溶液冷卻 至〇°C，且在使反應溫度維持在低於2.5°C之速率添加溴化 乙基鎂（1.888毫升，5.66毫莫耳）。使反應在氮氣中及〇。〇下 攪拌1 5分鐘’接著以二氧化碳氣流終止反應。使反應濃縮 成固體且添加乙酸（0.60毫升，10.48毫莫耳）及乙酸乙酯（50 127788.doc -159- 200840567 毫升），且使懸浮液在室溫下劇烈攪拌1 5分鐘。過濾所得 固體且以額外1 5毫升乙酸乙酯洗滌。使殘留物溶於1 〇毫升 水中，加入2 N HC1使之成為pH 4，接著以1 〇毫升乙醚洗 滌2次，再以4x20毫升CH2C12萃取。以硫酸鈉使合併之有 機萃取液乾燥，經過濾且減壓乾燥，獲得發泡體之3 -甲基-5,6-二氫-811-咪唑并[1，24]吼嗪-2,7-二甲酸7-苄酯（374毫 克 ’ 52%)。LCMS(表 1，方法a) Rt=2.28 min，m/z 316.10 (M+H)+'，NMR (400 MHz，DMSO-d6) δ 7.35 (m，5H)， 5·11 (s，2H)，4.56 (s，寬峰，2H)，3.88 (m，2H)，3.83 (s，寬 峰，2H)，2·36 (s，3H)。 實例編號27 : 2_【3-(3-氯-4-異丙氧基-苯基）_丨1，2,4】崎二唑- S-基卜3_甲基_5,6-二氫-8H-咪唑并[l，2-a】吡嗪_7_甲酸苄酯 之製備Anhydrous THF containing 2-iodo-3-methyl-5,6-dihydroimidazo[i,2-a]pyrazine-7(8H)-benzyl phthalate (900 mg, 2.266 mmol) The (25 ml) solution was cooled to 〇 ° C and ethylmagnesium bromide (1.888 mL, 5.66 mmol) was added at a rate to maintain the reaction temperature below 2.5 °C. The reaction was allowed to stand in nitrogen. The mixture was stirred for 15 minutes under the arm' and then quenched with a stream of carbon dioxide. The reaction was concentrated to a solid and acetic acid (0.60 mL, 10.48 mmol) and ethyl acetate (50 127 788. The resulting solid was filtered and washed with additional 15 mL ethyl acetate. The residue was dissolved in 1 mL of water, 2N HCl was added to pH 4, then washed twice with 1 mL of diethyl ether and then extracted with 4×20 mL of CH2C12. The combined organic extracts were dried over sodium sulfate, filtered and dried under reduced pressure to give &lt;&quot;&quot;&&&&&&&&&&&&&&&&&& - 7-Benzyl dicarboxylate (374 mg '52%). </ RTI> <RTI ID , 4.56 (s, broad peak, 2H), 3.88 (m, 2H), 3.83 (s, broad peak, 2H), 2·36 (s, 3H). Example No. 27: 2_[3-(3-Chloro-4-isopropoxy-phenyl)_丨1,2,4] Soxadiazole-S-Kib3_Methyl_5,6-Dihydro Preparation of -8H-imidazo[l,2-a]pyrazine-7-carboxylic acid benzyl ester

於各7 (十基氧基戴基）_3 -甲基- 5,6,7,8-四氫咪〇坐并[l，2-a]吡嗪-2-曱酸（37〇毫克，^73毫莫耳）之dcm(i〇毫升）溶 液中添加草醯氣（2〇54毫升，23·47毫莫耳）及〇^^(5微 升）。使反應攪拌一小時且濃縮。添加含（Ε)_3_氯羥基_ 4-異丙氧基笨甲脒（268毫克，hl73毫莫耳）之咄啶（ι〇•⑽毫 升）溶液且使反應在室溫下攪拌3〇分鐘。反應以乙醯氯 127788.doc 200840567In each 7 (decyloxydyl)_3-methyl-5,6,7,8-tetrahydropyrimidine and [l,2-a]pyrazine-2-furic acid (37 mg, ^ Grass dampness (2〇54 ml, 23.47 mmol) and 〇^^ (5 μL) were added to a solution of 73 mmol (dm). The reaction was allowed to stir for one hour and concentrated. Add a solution of (Ε)_3_chlorohydroxy-4- 4-isopropoxycarbenamide (268 mg, hl73 mmol) in acridine (ι〇•(10) mL) and allow the reaction to stir at room temperature for 3 min. . Reaction with acetonitrile chloride 127788.doc 200840567

(0·092毫升，1,291毫莫耳）處理且接著在115°C下及氮氣中 加熱4小時。使反應冷卻，經濃縮且分溶於飽和Na2C03及 二氣曱烷中。有機層以水洗滌，經脫水（硫酸鈉）、過濾且 減壓濃縮。使殘留物在矽膠上使用8〇:2〇/二氣甲烷：乙酸乙 酉旨作為溶離液純化，獲得灰白色固體之2^3-(3_氯_4_異丙 氧基-苯基）-[1，2,4]崎二唑-5-基]-3-曱基-5,6-二氫-8H-咪唑 并[l，2-a]。比嗪-7-曱酸苄酯（173毫克，29%)。LCMS(表1， 方法 a) Rt=4.34 min，m/z 508.24 (M+H)+-;】H NMR (400 MHz，DMSO-d6) δ 7·98 (d，1H)，7·93 (d，d，1H)，7.35 (m， 6H)，5.12 (s，2H)，4·78 (m，1H)，4.66 (s，寬峰，2H)，3.99 (m，2H)，3·88 (s，寬峰，2H)，2·57 (s，3H)，1.31 (d，6H)。 實例編號28 : 2-[3-(3-氯-4-異丙氧基苯基）-【i，2,4】，号二唑-基卜3_甲基·5,6,7,8·四氫_咪唑并p，2”】吡嗪之製備(0. 092 ml, 1,291 mmol) was treated and then heated at 115 ° C for 4 hours under nitrogen. The reaction was cooled, concentrated and taken up in saturated Na.sub.3CO. The organic layer was washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on silica gel using 8 〇: 2 〇 / di- ethane methane: ethyl acetate was purified as a solvent to afford 2^3-(3_chloro_4_isopropoxy-phenyl)-[ 1,2,4] Soxadiazol-5-yl]-3-indolyl-5,6-dihydro-8H-imidazo[1,2-a]. Benzazine-7-benzyl citrate (173 mg, 29%). LCMS (Table 1, Method a) Rt = 4.34 min, m/z 508.24 (M+H)+-;]H NMR (400 MHz, DMSO-d6) δ 7·98 (d,1H),7·93 ( d,d,1H), 7.35 (m, 6H), 5.12 (s, 2H), 4·78 (m, 1H), 4.66 (s, broad, 2H), 3.99 (m, 2H), 3.88 (s, broad peak, 2H), 2.57 (s, 3H), 1.31 (d, 6H). Example No. 28: 2-[3-(3-Chloro-4-isopropoxyphenyl)-[i,2,4], diazol-yl b-3-methyl·5,6,7,8 · Preparation of tetrahydro-imidazolium p,2"]pyrazine

使於含三異丙基矽烷（〇〇65毫升，〇·315毫莫耳）之乙酸 溶液（2.00毫升）中之含2办（3备4·異丙氧基苯基η，2,4』号 二唾-5-基&gt;3-曱基_5,6-二氫咪唑并[❻小比嗪_7(8η)甲酸 苄酯（160毫克，0.315毫莫耳）之33% HBr&lt;溶液在室溫下 及鼠氣中擾拌10分鐘。、添加乙絶(2〇毫升）使產物沉澱。過 濾所得固體’以飽和錢氫鈉溶液（1()毫升）洗滌且以二氯 甲烧（2x10毛升）萃取。合冑之有機層以硫酸鈉脫水，經過 濾、濃縮成固體且減壓乾燥，獲得灰白色固體之2-[3_(3_ 127788.doc -161 - 200840567 氣-4-異丙氧基苯基）-[1，2,4]嘮二唑-5-基&gt;3-甲基-5,6,7,8-四 氫-咪嗤并[l，2-a]吡嗪（113毫克，96%)。LCMS(表1，方法 a) Rt=3.14 min5 m/z 374.24 (M+H)+'; lU NMR (400 MHz? DMSO_d6) δ 8.01 (d，1H)，7.97 (d，d，1H)，7·36 (d，1H)，4.81 (m，1H)，4.66 (s，2H)，3.90 (s，2H)，3.87 (t，2H)，3·12 (t， 2H)，2.60 (s，3H)，1.34 (d，6H)。 實例編號29 : l-{2-[3-(3-氣-4-異丙氧基_苯基）-[i，2,4]噚二 唑-5-基]-3-甲基-5,6-二氫-8H-咪唑并[l，2-a]吡嗪-7-基卜乙 酮之製備In a solution of acetic acid (2.00 ml) containing triisopropyl decane (〇〇65 ml, 〇·315 mmol), 2 (3, 4, 4 isopropyloxyphenyl η, 2, 4) No. 2 bis-5-yl&gt; 3-mercapto-5,6-dihydroimidazo[33% bromopyrazine-7 (8η) benzyl formate (160 mg, 0.315 mmol) 33% HBr &lt; solution The mixture was stirred for 10 minutes at room temperature and in a mouse atmosphere, and the product was precipitated by adding diethyl ether (2 ml). The solid obtained was filtered and washed with saturated sodium hydrogen carbonate solution (1 ml) and then evaporated. 2x10 liters of extraction. The organic layer of hydrazine was dehydrated with sodium sulfate, filtered, concentrated to a solid and dried under reduced pressure to give 2-[3_(3_127788.doc-161 - 200840567 gas-4-isopropyl Oxyphenyl)-[1,2,4]oxadiazol-5-yl&gt;3-methyl-5,6,7,8-tetrahydro-imidin[l,2-a]pyrazine (113 mg, 96%). LCMS (Table 1, Method a) Rt=3.14 min5 m/z 374.24 (M+H)+'; lU NMR (400 MHz? DMSO_d6) δ 8.01 (d,1H), 7.97 ( d,d,1H),7·36 (d,1H),4.81 (m,1H),4.66 (s,2H),3.90 (s,2H),3.87 (t,2H),3·12 (t, 2H), 2.60 (s, 3H), 1.34 (d 6H). Example No. 29: l-{2-[3-(3-Gas-4-isopropoxy-phenyl)-[i,2,4]oxadiazol-5-yl]-3-A Preparation of keto-5,6-dihydro-8H-imidazo[l,2-a]pyrazine-7-yl-bethyl ketone

在室溫下於含2-(3-氣-4-異丙氧基苯基）-3-甲基-5,6,7,8-四氫咪嗤并[l，2-a]吡嗪（32毫克，0.105毫莫耳）之二氣曱烷 (2.0¾升）溶液中添加乙醢氣（7·5〇微升，〇1〇5毫莫耳）。使 混合物在室溫下攪拌4小時且濃縮。使殘留物經逆相hplc 純化，獲得灰白色固體之氣-4-異丙氧基-苯基）_ [1，2,4]嘮二唑-5-基]-3 -甲基-5,6-二氫- 8H-咪唑并[l，2-a]吡 嗓-7_基}-乙_ (31毫克，86%)。[CMS(表1，方法a) Rt=3.46 min, m/z 416.20(M+H)+; lH NMR (400 MHz? DMSO-d6) δ 8.02 (d，1H)，8.97 (d，d，1H)，7.37 (d，1H)，4,81 (m，2H)，4.70 (s，2H)，3·90 (s，2H)，4.07 (tOm，1H)，3.95 (m，3H)，2·62 (s，3H)，2.14 (m，3H)，1.34 (d，6H)。 實例編號30 : {2-[3-(3-氣·4-異丙氧基-苯基）-[l，2,4]，号二唑- 127788.doc •162- 200840567 5_基l·3-甲基-S，6-二氫咪唑并丨l，2-a]吡嗪-7-基卜乙酸 第三丁酯之製備2-(3-Ga-4-isopropoxyphenyl)-3-methyl-5,6,7,8-tetrahydroimieno[l,2-a]pyrazine at room temperature (32 mg, 0.105 mmol) of dioxane (2.03⁄4 liter) was added with acetonitrile (7.5 liters microliters, 〇1 〇 5 millimoles). The mixture was stirred at room temperature for 4 hours and concentrated. The residue was purified by reverse phase hplc to afford (4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-5,6 as an off-white solid. -Dihydro-8H-imidazo[l,2-a]pyridin-7-yl}-ethyl (31 mg, 86%). [CMS (Table 1, Method a) Rt = 3.46 min, m/z 416.20 (M+H) +; lH NMR (400 MHz? DMSO-d6) δ 8.02 (d, 1H), 8.97 (d, d, 1H) ), 7.37 (d, 1H), 4, 81 (m, 2H), 4.70 (s, 2H), 3.90 (s, 2H), 4.07 (tOm, 1H), 3.95 (m, 3H), 2· 62 (s, 3H), 2.14 (m, 3H), 1.34 (d, 6H). Example No. 30: {2-[3-(3-Gas-4-isopropoxy-phenyl)-[l,2,4], No. Diazole - 127788.doc •162- 200840567 5_基l· Preparation of 3-methyl-S,6-dihydroimidazolium, 1,2-a]pyrazine-7-ylacetic acid, tert-butyl ester

在室溫下於含3-(3-氣-4-異丙氧基苯基）-5-(3-甲基-5,6,7,8-四氫咪唑并[1，2-&amp;]吡嗪-2_基）-1，2,4-4二唑（50.0毫 克’ 〇·134毫莫耳）2DMf(i〇毫升）溶液中，添加碳酸鈉 (28.4宅克’ 0.267毫莫耳）及溴乙酸第三丁酯（〇·〇2ΐ毫升， 0· 140宅莫耳）。反應持續隔夜。反應經過濾且濃縮。使殘 留物溶於乙酸乙酯（1〇毫升）中，以鹽水〇〇毫升）洗滌，以 硫酸納脫水，經過濾且濃縮，獲得灰白色發泡體之{2_[3_ (3-氯-4-異丙氧基_苯基η124]呤二唑_5基]3甲基_56_二 氫-8Η-味唾并[na]吡嗪·7-基乙酸第三丁酯（35毫克， 54%) ’其可未經進一步純化用於下一步驟中。lcms(表 1 ’ 方法a) Rt=4.32 min，m/z 488.29 (M+H)+ 〇 實例編號37 : {2-丨3_(3_氣_4_異丙氧基苯基H1，2,4】呤二唑_ 5-基卜3-甲基_5,6-二氫·8H-咪唑并【ny吡嗪_7_基卜乙酸， 三氟乙酸鹽之製備3-(3-Ga-4-isopropoxyphenyl)-5-(3-methyl-5,6,7,8-tetrahydroimidazo[1,2-&amp; ]pyrazine-2_yl)-1,2,4-4 diazole (50.0 mg '〇·134 mmol) 2DMf (i 〇 ml) solution, adding sodium carbonate (28.4 Zirk '0.267 mmol) And tributyl bromoacetate (〇·〇2ΐ ml, 0·140 house Moule). The reaction continued overnight. The reaction was filtered and concentrated. The residue was dissolved in ethyl acetate (1 mL) and washed with EtOAc EtOAc EtOAc EtOAc EtOAc Isopropoxy-phenyl η124]oxadiazole_5yl]3 methyl_56_dihydro-8Η-flavored [na]pyrazine·7-glycolic acid tert-butyl ester (35 mg, 54% 'It can be used in the next step without further purification. lcms (Table 1 'Method a) Rt=4.32 min, m/z 488.29 (M+H)+ 〇Example No. 37: {2-丨3_(3 _ gas_4_isopropoxyphenyl H1,2,4]oxadiazole_ 5-kib-3-methyl_5,6-dihydro·8H-imidazo[nypyrazine_7_gib Preparation of acetic acid, trifluoroacetate

在至’里下於含2-(2-(3-(3-氣異丙氧基苯基）-1，2,4-咩二 嗤士基甲基一5,6-二氫味°坐并[Ih]吼嗪-7(8H)-基）乙酸 127788.doc -163- 200840567 第二丁酷（32毫克，〇·〇66毫莫耳）及三異丙氧基矽烷（0.013 宅升’ 0.066毫莫耳）之二氣曱烷（2〇毫升）溶液中添加 TFA(2.0毫升）歷時3小時。反應以乙醚（2〇毫升）稀釋且過濾 產物並減壓乾燥。LCMS(表1，方法a) Rt=2.99 min，m/z 432.23 (Μ+Η)+·;NMR (400 MHz，DMSO-d6) δ 8.0 (m， 2H)，7.36 (m，1H)，4·81 (m，1H)，3.97 (m，2H)，3.84 (m， 2H)，3.46 (m，2H)，3.09 (m，2H)，2.59 (s，3H)，1·33 (d， 6H)。 製備例編號17 · 2·甲基-味嗤并[i，2-a】《比唤-3-甲酸乙醋Sit under the 'into the 2-(2-(3-(3-isopropoxyphenyl)-1,2,4-indenyl)-methyl-5,6-dihydrogen And [Ih]pyridazine-7(8H)-yl)acetic acid 127788.doc -163- 200840567 Second Dingkuo (32 mg, 〇·〇66 mmol) and triisopropoxy decane (0.013 Zhaisheng' TFA (2.0 mL) was added to a solution of EtOAc (2 mL). a) Rt=2.99 min, m/z 432.23 (Μ+Η)+·; NMR (400 MHz, DMSO-d6) δ 8.0 (m, 2H), 7.36 (m, 1H), 4·81 (m, 1H) ), 3.97 (m, 2H), 3.84 (m, 2H), 3.46 (m, 2H), 3.09 (m, 2H), 2.59 (s, 3H), 1·33 (d, 6H). · 2·Methyl-Miso and [i,2-a]

使含吡嗪-2-胺（3·6克，37.9毫莫耳）及2-氯-3_側氧基丁酸 乙酯（5·24毫升，37·9毫莫耳）之乙醇（3〇毫升）溶液回流加熱 9小犄。添加含1 N HC1之乙醚溶液且減壓濃縮混合物。殘 留物以3x50毫升乙腈研散並過濾，獲得粗製無定型固體之 2-甲基-咪唑并[l，2-a]吡嗪-3 -曱酸乙酯（4·5克，58%)，其可 未經進一步純化用於下一步驟中。 製備例編號18 · 2_甲基-咪嗤并[1，2«^]0比嗓3-甲酸Ethanol containing pyrazin-2-amine (3.6 g, 37.9 mmol) and ethyl 2-chloro-3-oxetoxybutyrate (5·24 ml, 37·9 mmol) 〇ml) The solution was heated under reflux for 9 hours. A solution of 1 N HCl in diethyl ether was added and the mixture was concentrated under reduced pressure. The residue was triturated with 3×50 ml of acetonitrile and filtered to give ethyl 2-methyl-imidazo[l,2-a]pyrazine-3- decanoate as a crude amorphous solid (4.5 g, 58%). It can be used in the next step without further purification. Preparation No. 18 · 2_Methyl-Mimi-[1,2«^]0 is more than 嗓3-formic acid

127788.doc -164- 200840567 克，21.93毫莫耳）中。反應為放熱且在未額外加熱下於數 分鐘内趨向於完全。混合物以濃HC1酸化至pH 5。將溶液 注射入製備性C18管柱中並以水洗滌，且接著以2〇0/〇 CHAN/水溶離。合併產物溶離份並濃縮，獲得褐色固體 之2-曱基-咪唑并[u-a]咄嗪_3_甲酸（25〇毫克，6%)。 LCMS(表 1，方法a) Rt=〇84 min，176.18 (M-H)-; 4 NMR (400 MHz, DMS〇.d6) δ 9.12 (m? 2H)? 8.12 (m? 1H)5 2.66 (s，3H)。 實例編號31 : 3-[3-(3_氣_4·異丙氧基-苯*Hi，24]呤二唑· 5_基】甲基-咪唑并[l，2-a]吡嗪之製備127788.doc -164- 200840567 grams, 21.93 millimoles). The reaction is exothermic and tends to be complete within a few minutes without additional heating. The mixture was acidified to pH 5 with concentrated HCl. The solution was injected into a preparative C18 column and washed with water and then dissolved at 2 〇 0 / CHAN CHAN / water. The product fractions were combined and concentrated to give 2-bromo-imidazo[u-a]pyridazin-3-carboxylic acid (25 mg, 6%) as a brown solid. LCMS (Table 1, Method a) Rt = 〇 84 min, 176.18 (MH)-; 4 NMR (400 MHz, DMS 〇.d6) δ 9.12 (m? 2H)? 8.12 (m? 1H)5 2.66 (s, 3H). Example No. 31: 3-[3-(3_gas_4·isopropoxy-benzene*Hi,24]oxadiazole·5-yl]methyl-imidazo[l,2-a]pyrazine preparation

在室溫下以Hunig’s鹼（0·542毫升，3 1〇毫莫耳）及hatu (590毫克’ 1，552毫莫耳）處理含2_甲基咪唑并[丨，^]吼嗪_ 3-曱酸（250毫克’ 1.411毫莫耳kDCE(5毫升）溶液歷時^ 分鐘及在贼下歷㈣分鐘。濃駭應且使殘留物溶於乙 酸（1〇宅升）中且在100°c下加熱45分鐘。使反應冷卻至室溫 並減麼濃縮。使殘留物分溶於飽和碳酸鈉溶液（1〇毫升）及 二氣甲烧（2x10毫ff)中。有機層以硫酸納脫水，經過遽且 減壓濃縮。使殘留物在石夕膠上使用9:1/CH2Cl2:MeOH純 化。合併產物溶離份且減壓濃縮，獲得褐色固體之3_[3_ (3·氯冰異丙氧基·苯基Hl，2,4]号二唾_5_基K甲基十坐 并[1,2-a]17比嗓（133¾ 克，25%)。 127788.doc -165- 200840567 LCMS(表 1，方法a) Rt=4.31 min，m/z 370.25 (M+H)+; NMR (400 MHz，DMSO-d6) δ 9·43 (d，d，1H)，9.26 (d，1H)， 8.30 (d，1H)，8.21 (d，1H)，8.10 (d，d，1H)，7.40 (d，1H)， 4·84 (m，1H)，2·84 (s，3H)，1.36 (d，6H)。 實例編號32 : 3-(3-氣·4-異丙氧基苯基）-5-(4-((2,2-二甲基-工，3-二氧雜環戊-4-基）甲氧基）苯基）-1，2,4-，号二嗤之製備Treatment of 2-methylimidazo[丨,^]pyridazines with Hunig's base (0.542 ml, 31 mM mmol) and hadu (590 mg '1,552 mmol) at room temperature - citric acid (250 mg ' 1.411 mM kDCE (5 ml) solution for 2 minutes and in the thief (four minutes). Concentrate should be dissolved in acetic acid (1 〇 升) and at 100 ° c The mixture was heated for 45 minutes. The reaction was cooled to room temperature and concentrated. The residue was dissolved in saturated sodium carbonate (1 mL) and hexanes (2×10 ff). After hydrating and concentrating under reduced pressure, the residue was purified eluted eluted eluted eluted eluted eluted • Phenyl Hl, 2, 4] di-salt-5-yl K-methyl-spin and [1,2-a]17-specific oxime (1333⁄4 g, 25%). 127788.doc -165- 200840567 LCMS (Table 1, method a) Rt = 4.31 min, m / z 370.25 (M + H) +; NMR (400 MHz, DMSO-d6) δ 9·43 (d, d, 1H), 9.26 (d, 1H), 8.30 (d,1H), 8.21 (d,1H), 8.10 (d,d,1H), 7.40 (d,1H), 4·84 (m,1H),2·84 (s, 3H), 1.36 (d, 6H). Example No. 32: 3-(3-Gas-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-) Of 3-(2-dioxolan-4-yl)methoxy)phenyl)-1,2,4-,difluorene

在25毫升微波管中將4-((2,2-二甲基-1，3-二氧雜環戊-4-基）甲氧基）苯甲醯氣（0.483克，1.784毫莫耳）及〇3_氯-N*-羥基-4-異丙氧基苯曱脒（0.272克，1.189毫莫耳）於吡啶 (1 5毫升）中混合，獲得橘色溶液。將該管蓋住且以微波幅 射（Biotage Optimizer，300 W)在 200°C 下加熱20分鐘。使混 合物冷卻，移除溶劑，獲得黃色固體，使之分溶於水（100 毫升）及EtOAc(50毫升）中，以EtOAc(2x30毫升）萃取，合 併之EtOAc層以水（2x30^升）洗條並濃縮，獲得黃色固 體，使之經矽膠層析（40g，30% EtOAc :庚烷）純化，獲得 白色固體之3-(3•氯-4-異丙氧基苯基）-5-(4-((2,2-二甲基-^3-二氧雜環戊-4-基）曱氧基）苯基）-i，2,4-嘮二唑（0.3克， 0·674 毫莫耳，產率 56.7%)。LC/MS (30—95 NH4OAc 4m GC8.olp) R，=3.22 min.; MS m/z: 445·31 (Μ+Η)+· NMR (400 MHz,溶劑 d-DMSO) δ ppm 8.17-8.09 (m，2H)， 8·〇5 (d，&gt;2·13 Hz，1H)，7·99 (dd，J二8·64，2.15 Hz，1H)， 127788.doc -166- 200840567 7.38 (d, /=9.01 Hz, 1H), 7.26-7.19 (m, 2H), 4.88-4.77 (m, 1H), 4.45 (s, 1H), 4.23-4.07 (m, 3H), 3.79 (dd, J=8.42, 6.29 Hz，1H)，1·35 (m，12H) 〇 製備例編號19 : 2-(4-(氣羰基）苯氧基）乙酸第三丁酯 〇丫 OH 0 0 φο ,— 於H)0毫升圓底瓶中將4_(2_第三丁氧基_2_側氧基乙氧基） 苯甲酸（0.76克’ 3.01毫莫耳）添加於二氯甲烷（3〇丨毫升） 中，獲得無色懸浮液。將五滴DMF添加於溶液中。反應混 合物以冰浴冷卻。滴加草醯氯（0,396毫升，4.52毫莫耳）。 移開冰浴且使溶液在室溫下攪拌40分鐘。濃縮反應混合 物，獲得無色油之2-(4-氯羰基）苯氧基）乙酸第三丁酯（〇·86 克。3.18宅莫耳’產率 105%)。4 NMR (400 MHz，CDC/3) δ ppm 8·1〇 (d，2H)，6·95 (d，2H)，4.61 (s，2H)，1.49 (s， 9H)。 實例编號33 : 2-(4-(3-(h氣異丙氧基苯基）β1，2,4_噚二 唑-5-基）苯氧基）乙酸之製備4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)benzhydrazide (0.483 g, 1.784 mmol) in a 25 mL microwave tube And 〇3_chloro-N*-hydroxy-4-isopropoxyphenylhydrazine (0.272 g, 1.189 mmol) was mixed in pyridine (15 ml) to give an orange solution. The tube was covered and heated with a microwave radiation (Biotage Optimizer, 300 W) at 200 ° C for 20 minutes. The mixture was cooled, EtOAc (EtOAc) (EtOAc m. The residue was concentrated to give EtOAc (EtOAc m. 4-((2,2-Dimethyl-^3-dioxolan-4-yl)decyloxy)phenyl)-i,2,4-oxadiazole (0.3 g, 0·674 m Moule, yield 56.7%). LC/MS (30-95 NH4OAc 4m GC8.olp) R,=3.22 min.; MS m/z: 445·31 (Μ+Η)+· NMR (400 MHz, solvent d-DMSO) δ ppm 8.17-8.09 (m, 2H), 8·〇5 (d, &gt; 2·13 Hz, 1H), 7·99 (dd, J 2·8·64, 2.15 Hz, 1H), 127788.doc -166- 200840567 7.38 ( d, /=9.01 Hz, 1H), 7.26-7.19 (m, 2H), 4.88-4.77 (m, 1H), 4.45 (s, 1H), 4.23-4.07 (m, 3H), 3.79 (dd, J= 8.42, 6.29 Hz, 1H), 1·35 (m, 12H) 〇Preparation No. 19: 2-(4-(V) phenoxy)acetic acid tert-butyl ester 〇丫OH 0 0 φο , — in H 4_(2_Tertioxy-2-oxaoxyethoxy)benzoic acid (0.76 g '3.01 mmol) was added to dichloromethane (3 mL) in a 0 mL round bottom flask , obtaining a colorless suspension. Five drops of DMF were added to the solution. The reaction mixture was cooled in an ice bath. Grass chloroform (0,396 ml, 4.52 mmol) was added dropwise. The ice bath was removed and the solution was stirred at room temperature for 40 minutes. The reaction mixture was concentrated to give a tri-butyl 2-(4-chlorocarbonyl)phenoxy)acetate (yield: 86 g. 4 NMR (400 MHz, CDC/3) δ ppm 8·1 〇 (d, 2H), 6.95 (d, 2H), 4.61 (s, 2H), 1.49 (s, 9H). Example No. 33: Preparation of 2-(4-(3-(h-isopropoxyphenyl)β1,2,4-oxadiazol-5-yl)phenoxy)acetic acid

於25毫升微波反應瓶中饋入2-(4-(氯羰基）笨氧基）乙酸第 三丁酯（0.8 15克，3.01毫莫耳）及吡啶（15毫升），添加（z)-3- 127788.doc -167- 200840567 氣-Ν’ -經基-4-異丙氧基苯甲肺（0·459克，2·007毫莫耳）。將 該瓶蓋住且以微波幅射（Biotage Optimizer，300 W)使反應 在200°C下加熱20分鐘。使混合物冷卻，將反應混合物倒 入攪拌之HC1( 10%，100毫升）中，過濾所得懸浮液，固體 以HC1 (5%，2x10毫升）洗滌並乾燥，獲得灰色固體，使之 經RP-HPLC(A=50 mM 乙酸敍，B=乙腈；30-95%B歷時 25.0 分鐘（流速 21.0 毫升/分鐘）；21.2x250mm Thermo Hyperprep Cl 8管柱，8 μηι粒子）純化，獲得白色固體之2-(4-(3-(3-氣-4-異丙氧基苯基）-152,4-嘮二唑-5-基）苯氧基）乙酸（0,246 克，0.633毫莫耳，產率31.5%)。LC/MS(方法F) R尸2·08 min·; MS m/z: 389.14 (Μ+Η)+。4 NMR (400 ΜΗζ，溶劑心 DMSO) δ ppm 13.28-13.07 (m? 1H), 8.13 (d? J=9.03 Hz5 2H)，8.05 (d，&gt;2.13 Hz，1H)，7.99 (dd，&gt;8.64, 2.15 Hz， 1H)，7.38 (d，/=9.04 Hz，1H)，7·18 (d，&gt;9.06 Hz，2H)，4.85 (s，3H)，1·35 (d，J=6.03 Hz，6H)。 實例編號34 : 5-(6-(lH-苯并叫【1，2,3]三唑-1_基氧基）吡啶_ 3-基）-3-(3_氣-4-異丙氧基苯基）-1，2,4-崎二嗤之製備Twenty-butyl 2-(4-(chlorocarbonyl)phenyloxy)acetate (0.815 g, 3.01 mmol) and pyridine (15 ml) were added to a 25 ml microwave reaction vial, and (z)-3 was added. - 127788.doc -167- 200840567 Gas-Ν'-trans--4-isopropoxyphenyl-lung lung (0·459 g, 2.007 mmol). The bottle was capped and the reaction was heated at 200 ° C for 20 minutes with microwave irradiation (Biotage Optimizer, 300 W). The mixture was cooled, and the mixture was poured into EtOAc EtOAc EtOAc (EtOAcjjjjjjjj (A = 50 mM acetic acid, B = acetonitrile; 30-95% B for 25.0 minutes (flow rate 21.0 ml / min); 21.2 x 250 mm Thermo Hyperprep Cl 8 column, 8 μηι particles) was purified to obtain a white solid 2- 4-(3-(3-Ga-4-isopropoxyphenyl)-152,4-oxadiazol-5-yl)phenoxy)acetic acid (0,246 g, 0.633 mmol, yield 31.5%) ). LC/MS (Method F) R corp. 2·08 min·; MS m/z: 389.14 (Μ+Η)+. 4 NMR (400 ΜΗζ, solvent core DMSO) δ ppm 13.28-13.07 (m? 1H), 8.13 (d? J=9.03 Hz5 2H), 8.05 (d, &gt; 2.13 Hz, 1H), 7.99 (dd,&gt; 8.64, 2.15 Hz, 1H), 7.38 (d, /=9.04 Hz, 1H), 7·18 (d, &gt; 9.06 Hz, 2H), 4.85 (s, 3H), 1·35 (d, J = 6.03) Hz, 6H). Example No. 34: 5-(6-(lH-Benzo[1,2,3]triazol-1_yloxy)pyridine-3-yl)-3-(3_--4-isopropyloxy Preparation of phenyl)-1,2,4-sodium bismuth

於25毫升微波反應藥瓶中饋入（Z)-3-氯-N，-羥基-4-異丙 氧基苯曱脒（〇·1克，〇·437毫莫耳），6_溴菸鹼酸（〇 097克， 0.481毫莫耳）及DCC(0.099克，0.481毫莫耳）之乙腈（2,403 宅升）。一次添加HOBT(0.074克，0.48 1毫莫耳），使所得 I27788.doc -168 - 200840567 懸浮液在室溫下攪拌10分鐘。滴加DIEA(0.168毫升， 0.962毫莫耳），以微波幅射（Biotage Optimizer，300 W)使反 應混合物在120°C下加熱30分鐘。使溶液冷卻，將反應混 合物分溶於EtOAc(50毫升）及水（50毫升）中，有機層以水 (2x50耄升）洗滌，並濃縮獲得黃色固體，使之經石夕膠層析 (12克，20% EtOAc :庚烷）純化，獲得白色固體之5·(6_ (1Η-苯并[d][l，2,3]三唑-1-基氧基）吼啶-3-基）-3-(3-氯-4-異 丙氧基苯基）-1，2,4·嘮二唑（0.128克，0.285毫莫耳，產率 65.2%)。LC/MS(方法 A) R，=3.74 min·; MS m/z: 449.18 (Μ+Η)+· NMR (400 MHz，溶劑· d-DMSO) ppm 8·88 (dd， J=2.25, 0.65 Hz，1H)，8.62 (dd，&gt;8.68, 2·27 Hz，1H)，8·15 (t，/=5.28 Hz，2H)，7·97 (dd，J二8·62, 2·14 Hz，1H)，7.55 (d， J=0.96 Hz，1H)，7.52-7.44 (m，2H)，7.36 (dd，《7=8.68，0.70 Hz，lH)，7.03(d，/=8.87Hz，lH)，4.73-4.61(m，lH)，1.46-1.40 (m，6H)。 製備例編號20 : 0)-3_溴-1^-羥基-4-異丙氧基苯甲脒Feeding (Z)-3-chloro-N,-hydroxy-4-isopropoxyphenylhydrazine (〇·1 g, 〇·437 mmol) in a 25 ml microwave reaction vial, 6_bromo Alkaline acid (〇097 g, 0.481 mmol) and DCC (0.099 g, 0.481 mmol) of acetonitrile (2,403 liters). HOBT (0.074 g, 0.48 1 mmol) was added in one portion, and the resulting suspension of I27788.doc -168 - 200840567 was stirred at room temperature for 10 minutes. DIEA (0.168 ml, 0.962 mmol) was added dropwise, and the reaction mixture was heated at 120 ° C for 30 minutes with microwave irradiation (Biotage Optimizer, 300 W). The solution was cooled and the residue was evaporated EtOAc mjjjjjjjjjjjjjjj Purification by EtOAc (20% EtOAc:EtOAc) 3-(3-Chloro-4-isopropoxyphenyl)-1,2,4·oxadiazole (0.128 g, 0.285 mmol, yield 65.2%). </ RTI> <RTI Hz, 1H), 8.62 (dd, &gt; 8.68, 2·27 Hz, 1H), 8·15 (t, /=5.28 Hz, 2H), 7·97 (dd, J 2: 8.62, 2·14 Hz, 1H), 7.55 (d, J = 0.96 Hz, 1H), 7.52-7.44 (m, 2H), 7.36 (dd, "7=8.68, 0.70 Hz, lH), 7.03 (d, /= 8.87 Hz, lH), 4.73-4.61 (m, lH), 1.46-1.40 (m, 6H). Preparation No. 20: 0)-3_Bromo-1^-hydroxy-4-isopropoxybenzamide

於EtOH(20毫升）中混合3-溴-4-異丙氧基苄腈（0.68克， 2.83毫莫耳）及羥基胺（0.208毫升，3·12毫莫耳）。使反應混 合物在65°C下加熱16小時。濃縮反應混合物獲得淺黃色固 體之（Ζ)-3·溴-NL羥基-4-異丙氧基苯甲脒（0.76克，2.78毫 莫耳，產率 98%)。LC/MS(方法 A) Rt =2.89 min·; MS m/z: 127788.doc -169- 200840567 275.00 (M+H)+。 實例編號35 : 4-(3-(3-溴-4-異丙氧基苯基）-1，2,4-噚二唑-5-基）苄腈之製備3-Bromo-4-isopropoxybenzonitrile (0.68 g, 2.83 mmol) and hydroxylamine (0.208 mL, 3.12 mmol) were combined in EtOH (20 mL). The reaction mixture was heated at 65 ° C for 16 hours. The reaction mixture was concentrated to give (yield) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Example No. 35: Preparation of 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile

於裝置有攪拌棒之25毫升微波藥瓶中饋入4-氰基苯曱醯 氣（〇·4克，2.416毫莫耳)、(Z)-3-溴-Ν'-羥基-4-異丙氧基苯 甲脒（0.5克，1.831毫莫耳）及吼啶（15毫升），獲得橘色溶 液。將該瓶蓋住且以微波幅射（Biotage Optimizer，300 W) 使反應在200°C下加熱20分鐘。使溶液冷卻，使反應混合 物分溶於HC1水溶液（10%，150毫升）及DCM(40毫升）混合 物中，傾倒掉DCM層，且以DCM(2x20毫升）萃取水層。合 併之DCM層以水（2x20毫升）洗滌並經濃縮，獲得白色固 體，使之經矽膠層析（40克，40%EtOAc :庚烷）純化，獲得 白色固體之4-(3-(3 -&gt;臭-4-異丙氧基苯基）-1， 基）苄腈（0.638克，1.660毫莫耳，產率91%)。LC/MS(方法 C) R^3.17 min.; MS m/z\ 386.19 (M+H)+. lU NMR (400 MHz，溶劑· d-DMSO) ppm 8.40-8.32 (m，2H)，8·23 (d， /=2.13 Hz，1H)，8·14 (dd，J=8.14，0·61 Hz，2H)，8.05 (dd， J=8.65，2.15 Hz，1H)，7.36 (d，/=9.12 Hz，1H)，4·89-4·77 O, 1H)，1.35 (d，/=6·03 Hz，6H)。 實例編號36· 4-(3-(3 -漠-4-異丙氧基苯基）-1，2，4 - 〃号二嗅- 5-基)苯甲醛之製備 127788.doc -170- 200840567Feeding 4-cyanobenzoquinone (〇·4 g, 2.416 mmol) and (Z)-3-bromo-Ν'-hydroxy-4-iso in a 25 ml microwave vial equipped with a stir bar Propyl benzophenone (0.5 g, 1.831 mmol) and acridine (15 mL) gave an orange solution. The bottle was capped and the reaction was heated at 200 ° C for 20 minutes with microwave irradiation (Biotage Optimizer, 300 W). The solution was allowed to cool and the mixture was taken from EtOAc EtOAc (EtOAc) The combined DCM layer was washed with EtOAc (EtOAc m. &gt; Omega-4-isopropoxyphenyl)-1,yl)benzonitrile (0.638 g, 1.660 mmol, yield 91%). LC/MS (method C) R^3.17 min.; MS m/z\ 386.19 (M+H)+. lU NMR (400 MHz, solvent, d-DMSO) ppm 8.40-8.32 (m,2H),8· 23 (d, /=2.13 Hz, 1H), 8·14 (dd, J=8.14, 0·61 Hz, 2H), 8.05 (dd, J=8.65, 2.15 Hz, 1H), 7.36 (d, /= 9.12 Hz, 1H), 4·89-4·77 O, 1H), 1.35 (d, /=6·03 Hz, 6H). Example No. 36· Preparation of 4-(3-(3-is-iso-4-isopropoxyphenyl)-1,2,4-anthracene two-smell-5-yl)benzaldehyde 127788.doc -170- 200840567

於裝置配備有氮氣輸入針頭之膈膜蓋之i 0Ό毫升圓底瓶 中饋入含4-(3-(3-溴-4-異丙氧基苯基4_哼二唑巧_基） 苄腈（0·64克，1.666毫莫耳）之DCM(33.3毫升），獲得無色 溶液。以乙腈-乾冰浴使反應混合物冷卻至_ 4 〇 °c且變成白 色懸浮液。於10分鐘内滴加Dibal-H(3.33毫升，3.33毫莫 耳）。使之在-4G C下再攪拌60分鐘。滴加曱醇（〇135毫 升，3.33耄莫耳）以終止反應。接著將全部混合物倒入攪拌 之Rochelle’s鹽（200毫升）中。使之在室溫下攪拌4小時，接 著使之分浴，水層以DCM(2x50毫升）萃取，合併之dcm層 以水（60宅升）洗條’以MgS〇4脫水。經過濾及濃縮，獲得 1·〇4克橘色油，使之經矽膠層析（4〇克，‘ο% EtOAc :庚 烷）純化，獲得淺黃色固體之4-(3-(3-溴-4·異丙氧基苯基）-1，2,4-嘮二唑-5-基）苯甲醛（〇·551克，U23毫莫耳，產率 min.; MS m/z: 388.94 &gt;谷劑· d-DMSO) ppm 10.15 85%)。LC/MS(方法 C) R,=3.17 (M+H)、巾 NMR (400 MHz，溶 (s, 1Η)? 8.41 (d5 /=8.20 Hz, 2H)5 8.24 (d, 7=2.13 Hz, 1H)? 8.20-8.14 (m，2H)，8.06 (dd5 J=8.64, 2.15 Hz，1H)，7.37 (d， J=9.11 Hz, 1H)? 4.89-4.78 6H)。 (m，1H)5 1.36 (d? 7=6.03 Hz5 實例編號37 : 3-(3-溴_4·異丙氧基苯基）-5-(4-(二甲氧基甲 基）苯基）·1，2,4·噚二唑之製備 I27788.doc -171 - 200840567Feeding 4-(3-(3-bromo-4-isopropoxyphenyl 4 oxadiazole) benzyl in a 0 0 ml round bottom bottle equipped with a helium cap of a nitrogen input needle Nitrile (0·64 g, 1.666 mmol) in DCM (33.3 mL) elute Dibal-H (3.33 ml, 3.33 mmol) was stirred at -4 G for an additional 60 minutes. Decanol (〇 135 mL, 3.33 mmol) was added dropwise to terminate the reaction. Then the whole mixture was poured into the mixture. Rochelle's salt (200 ml) was stirred at room temperature for 4 hours, then allowed to separate, the aqueous layer was extracted with DCM (2×50 mL), and the combined dcm layer was washed with water (60 liters) Dehydration of MgS〇4. Filtration and concentration gave 1 g of 4 g of orange oil, which was purified by silica gel chromatography (4 g, EtOAc, EtOAc) -(3-Bromo-4.isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (〇·551 g, U23 mmol, yield min.; MS m /z: 388.94 &gt; gluten · d-DMSO) ppm 10. 15 85%). LC/MS (Method C) R, = 3.17 (M+H), NMR (400 MHz, dissolved (s, 1 Η)? 8.41 (d5 / = 8.20 Hz, 2H) 5 8.24 (d, 7 = 2.13 Hz, 1H)? 8.20-8.14 (m, 2H), 8.06 (dd5 J=8.64, 2.15 Hz, 1H), 7.37 (d, J=9.11 Hz, 1H)? 4.89-4.78 6H). (m,1H)5 1.36 (d? 7=6.03 Hz5 Example No. 37: 3-(3-Bromo-4)isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl Preparation of 1,2,4·oxadiazole I27788.doc -171 - 200840567

原甲酸二甲酯（4毫升，36·2毫莫耳）及甲醇（6毫升）中，使 反應混合物在8〇°C下加熱16 hr 使溶液冷卻，濃縮反應混 合物獲得灰色固體，使之經矽膠層析（12克，2〇% Et〇Ac : 庚烷）純化，獲得白色固體之3气3_溴異丙氧基苯基 (4-(二甲氧基甲基）苯基）_ι，2,4-噚二唑（0.61克，1.366毫莫 耳’產率 96%)。LC/MS(方法 A) Rt=3.31 min·; MS m/z: 435,03 (M+H).。NMR (400 MHz，溶劑 d-DMSO) ppm 8.25-8.19 (m，3H)，8·05 (dd，J=8.63，2.14 Hz，1H)，7.67 (d， J=8.18 Hz，2H)，7.35 (d，7=9.02 Hz，1H)，5.52 (s，1H)， 4·86-4·78 (m，1H)，3.30 (s，6H)，1.35 (d，J=6.02 Hz，7H)。 實例編號38 : 5-(5-(4-(二甲氧基甲基）苯基）4,2,4·噚二唑-3-基）_2_異丙氧基苄腈之製備In dimethyl orthoformate (4 ml, 36.2 mmol) and methanol (6 ml), the reaction mixture was heated at 8 ° C for 16 hr to cool the solution, and the reaction mixture was concentrated to give a white solid. Purification by silica gel chromatography (12 g, 2% EtOAc: EtOAc) 2,4-oxadiazole (0.61 g, 1.366 mmol) yield 96%. LC/MS (Method A) Rt = 3.31 min.; MS m/z: 435, (M+H). NMR (400 MHz, solvent d-DMSO) ppm 8.25-8.19 (m, 3H), 8.05 (dd, J = 8.63, 2.14 Hz, 1H), 7.67 (d, J = 8.18 Hz, 2H), 7.35 ( d, 7 = 9.02 Hz, 1H), 5.52 (s, 1H), 4·86-4·78 (m, 1H), 3.30 (s, 6H), 1.35 (d, J = 6.02 Hz, 7H). Example No. 38: Preparation of 5-(5-(4-(dimethoxymethyl)phenyl)4,2,4.oxadiazol-3-yl)_2-isopropoxybenzonitrile

將3-(3 -溴-4 -異丙氧基本基）-5-(4-(二甲氧基甲基）苯基）-1，2,4-噚二唑（0.25克，0.577毫莫耳）、氰化銅0)(0^33克， 127788.doc -172- 200840567 1·485毫莫耳）及吼啶（15毫升）注入裝置有攪拌棒之25毫升 微波藥瓶中。將該瓶蓋住且以微波幅射（Biotage Optimizer, 300 W)將反應加熱至230°C歷時30分鐘。使溶液 冷卻，濃縮反應混合物，於殘留物中添加水合氯化鐵（0·8 克）、濃鹽酸（2毫升）及水（12毫升）。使溶液在65它下加熱 20分鐘，以DCM(3x30毫升）萃取水性混合物，合併之DCM 層以FeCU溶液（2x20毫升）洗條，接著以水（2x20毫升）洗 滌，經脫水（鹽水，MgS〇4)並經濃縮，獲得黃色固體，使 之經矽膠層析（40克，20%EtOAc :庚烧)純化，獲得淺黃色 固體之5-(5-(4-(二甲氧基甲基）苯基）-1，2，4-口号二唑-3-基）-2-異丙氧基苄腈（0.086克，0.227毫莫耳，產率39.3%)。 實例編號39 : 5-(5-(4_甲醯基苯基）-1，2,4-呤二唑_3_基）-2-異丙氧基苄腈之製備3-(3-Bromo-4-isopropoxybenzyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.25 g, 0.577 mmol) Ear), copper cyanide 0) (0^33 g, 127788.doc -172-200840567 1.485 mmol) and acridine (15 ml) were injected into a 25 ml microwave vial with a stir bar. The bottle was capped and the reaction was heated to 230 °C for 30 minutes with microwave radiation (Biotage Optimizer, 300 W). The solution was cooled, and the mixture was concentrated. EtOAc EtOAc (EtOAc) The solution was heated at 65 °C for 20 min, the aqueous mixture was extracted with DCM (3×30 mL), and the combined DCM layer was washed with FeCU solution (2×20 mL), then washed with water (2×20 ml), dehydrated (brine, MgS) 4) Concentration to give a yellow solid which was purified eluting eluting eluting eluting eluting Phenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.086 g, 0.227 mmol, yield 39.3%). Example No. 39: Preparation of 5-(5-(4-carbinophenyl)-1,2,4-oxadiazole-3-yl)-2-isopropoxybenzonitrile

將5-(5-(4-二甲氧基甲基）苯基）-1，2,4·咩二唑-3-基）-2-異 丙氧基苄腈（0.086克，0.227毫莫耳）及對-曱苯磺酸單水合 物（0·043克，0.227毫莫耳）添加於丙酮（10毫升）中，獲得無 色溶液。使反應混合物在60°C下加熱2 hr。使溶液冷卻， 濃縮反應混合物，使殘留物經石夕膠層析（12克，50% EtOAc/庚烷）純化，獲得白色固體之5-(5-(4-甲醯基苯基）· 1，2,4-咩二唑-3-基）-2-異丙氧基苄腈（0.077克，0.231毫莫 耳，產率 102%)。LC/MS(方法 F) R严2.88 min.; MS m/厂 127788.doc -173 - 200840567 334.08 (M+H)+ 〇 實例編號40 : 1-(4-(3-(3-氰基-4-異丙氧基苯基）4,2,4•噚二 唑_5_基）苄基）吖丁啶-3-甲酸之製備5-(5-(4-Dimethoxymethyl)phenyl)-1,2,4·oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.086 g, 0.227 mmol) The ear and p-toluenesulfonic acid monohydrate (0·043 g, 0.227 mmol) were added to acetone (10 ml) to give a colorless solution. The reaction mixture was heated at 60 °C for 2 hr. The solution was allowed to cool, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g, 0.231 mmol, yield 102%). LC/MS (Method F) R to be 2.88 min.; MS m / s 127788.doc - 173 - 200840567 334.08 (M+H) + 〇 Example No. 40: 1-(4-(3-(3-Cyano)- Preparation of 4-isopropoxyphenyl)4,2,4•oxadiazole-5-yl)benzyl)azetidine-3-carboxylic acid

在密封藥瓶中將5-(5-(4-甲醯基苯基）-1，2,4·-号二嗤_3_ 基）-2-異丙氧基苄腈（0·077克，〇·231毫莫耳）及吖丁咬_3_甲 酸（0.028克，0.277毫莫耳）於甲醇（11.55毫升）jDCE(11.55 宅升）中混合。添加乙酸（0.066毫升，1.155毫莫耳）。使反 應混合物在周圍溫度下攪拌2小時。添加MP-氰基硼氫化納 (0.265克，0.570毫莫耳）且使反應攪拌約24小時。過濾溶 液’以二氯甲烷及甲醇洗滌固體且濃縮濾液，獲得白色固 體，以甲醇（5毫升）使之再結晶，獲得白色固體之1_(4-(3_ (3-氰基-4-異丙氧基苯基）-1，2,4-$ 二唾-5-基）苄基）吖丁唆- 3 -甲酸（0.025克，0.060毫莫耳，產率25.9%)。LC/MS(方法 A) Rt=2.10 min·; MS m/z: 420.26 (M+H)+。4 NMR (400 MHz，溶劑· d-DMSO) ppm 8.35-8.28 (m，2H)，8·17-8·11 (d， /=8.00 Hz，2H)，7.56-7.50 (m，8.69 Hz，3H)，4·98-4·89 (m， 1H)，3·68 (s，2H)，3·43 (s，2H)，3·25-3·23 (m，3H)，1.38 (d， /=6.03 Hz，6H) 〇 實例編號41 : 1-(4-(3-(3-氣-4-異丙氧基苯基）-l，2,4-噚二 唑·5-基）苯基）環丙烷曱腈之製備 127788.doc -174- 2008405675-(5-(4-methylnonylphenyl)-1,2,4·-diindole-3-yl)-2-isopropoxybenzonitrile (0·077 g, in a sealed vial, 〇·231 mmol) and butyl _3_carboxylic acid (0.028 g, 0.277 mmol) were mixed in methanol (11.55 ml) jDCE (11.55 house liter). Acetic acid (0.066 mL, 1.155 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours. MP-Cyanoborohydride (0.265 g, 0.570 mmol) was added and the reaction was stirred for about 24 hours. The solution was filtered and the solid was washed with methylene chloride and methanol. EtOAc (EtOAc m. Oxyphenyl)-1,2,4-$disita-5-yl)benzyl)azinium-3-carboxylate (0.025 g, 0.060 mmol, yield 25.9%). LC/MS (method A) Rt = 2.10 min.; MS m/z: 420.26 (M+H)+. 4 NMR (400 MHz, solvent · d-DMSO) ppm 8.35-8.28 (m, 2H), 8·17-8·11 (d, /=8.00 Hz, 2H), 7.56-7.50 (m, 8.69 Hz, 3H ), 4·98-4·89 (m, 1H), 3·68 (s, 2H), 3·43 (s, 2H), 3·25-3·23 (m, 3H), 1.38 (d, /=6.03 Hz,6H) 〇Example No. 41: 1-(4-(3-(3-Ga-4-isopropoxyphenyl)-l,2,4-oxadiazole·5-yl)benzene Preparation of cyclopropanecarbonitrile 127788.doc -174- 200840567

將4-(1-氰基環丙基）苯甲酸（72〇毫克，3·85毫莫耳）' (z)_ 3-氯-Ν’-羥基-4-異丙氧基苯甲脒（88〇毫克，3·85毫莫耳）、 〇CC(873 毫克，4·23 毫莫耳）、ΗΟΒΊΓ(648 毫克，4.23 毫莫 耳）、ACN(10毫升）及DIEA(1.478毫升，8·46毫莫耳）饋入2〇 毫升微波藥瓶中。將該藥瓶蓋住且經微波幅射加熱至16〇 φ C歷時25分鐘（最大300 W)。減壓移除溶劑且使粗製油經 快速管柱層析（Analogix系統，庚烷/乙酸乙酯，〇-45%乙酸 乙酯歷時30分鐘；80克管柱，流速60毫升/分鐘）。合併含 產物之溶離份，經旋轉蒸發且於真空烘箱中乾燥隔夜，獲 知黃色固體之1-(4-(3-(3-氣-4-異丙氧基苯基）_ι，2,4-吟二 唑-5-基）苯基）環丙烷甲腈（347毫克，23,8%)。LCMS(表1， 方法 c) Rt=3.19 min，w/z 380.43 (M+H)+; 4 NMR (400 MHz，DMSO)J ppm 8.22-8.12 (m，2H)，8.05 (d，1H)，7.99 • (dd，2·14 Hz，1H)，7·62-7·55 (m，2H)5 7.38 (d，1H)，4.82 (td，1H)，1.90 (q，2H)，1.67 (q，2H)，1.38-1.33 (m，6H)。 實例編號42 : 1-(4-(3-(3-氣-4-異丙氧基苯基）_i，2,4…崎二 唑·5-基）苯基）環丙烷甲醛之製備4-(1-Cyanocyclopropyl)benzoic acid (72 mg, 3.85 mmol) '(z)_ 3-chloro-indole-hydroxy-4-isopropoxybenzidine ( 88 mg, 3.85 mmol, 〇CC (873 mg, 4·23 mmol), ΗΟΒΊΓ (648 mg, 4.23 mmol), ACN (10 ml) and DIEA (1.478 ml, 8· 46 millimoles) was fed into a 2 cc microwave vial. The vial was capped and heated by microwave radiation to 16 〇 φ C for 25 minutes (maximum 300 W). The solvent was removed under reduced pressure and the crude oil was subjected to flash column chromatography (Analogix system, heptane/ethyl acetate, &lt;RTI ID=0.0&gt;&gt; The product-containing fractions were combined, vortexed and dried in a vacuum oven overnight to give 1-(4-(3-(3- s) 4-isopropoxyphenyl). Oxazol-5-yl)phenyl)cyclopropanecarbonitrile (347 mg, 23, 8%). LCMS (Table 1, Method c) Rt = 3.19 min, w/z 380.43 (M+H)+; 4 NMR (400 MHz, DMSO) J. 7.99 • (dd, 2·14 Hz, 1H), 7·62-7·55 (m, 2H) 5 7.38 (d, 1H), 4.82 (td, 1H), 1.90 (q, 2H), 1.67 (q , 2H), 1.38-1.33 (m, 6H). Example No. 42: Preparation of 1-(4-(3-(3- gas-4-isopropoxyphenyl)_i, 2,4...soxadiazole·5-yl)phenyl)cyclopropanecarboxaldehyde

將1-(4·(3-(3 -氣-4-異丙氧基本基）-1，2，4-p号二嗤-5-基）苯 基）環丙烷甲腈（300毫克，0.790毫莫耳）及二氯甲烷（8毫升） 127788.doc •175- 2008405671-(4·(3-(3-(4-isopropoxy))-1,2,4-p-dioxa-5-yl)phenyl)cyclopropanecarbonitrile (300 mg, 0.790) Millol) and dichloromethane (8 ml) 127788.doc •175- 200840567

饋入100毫升圓底瓶中，且接著冷卻至-40°C。經針筒缓慢 添加DIBAL-H(0.869毫升，0.869毫莫耳）且使反應混合物 升溫至室溫隔夜。添加Me〇H(4毫升）及R0chelle，s鹽水溶液 (4毫升）終止反應。使層分離且以DCM(3x25毫升）萃取水 層。有機層以飽和碳酸氫鈉溶液洗滌，接著以MgS04脫水 並濃縮。於含粗製物質之3毫升THF溶液添加3毫升1N HC1。使混合物在室溫下攪拌1小時。使混合物經旋轉蒸發 移除THF。接著使該物質經快速管柱層析（Anal〇gix，4〇克 管柱，0-40%乙酸乙酯/庚烷歷時3〇分鐘，流速3〇毫升/分 鐘）。合併含產物之溶離份並經濃縮，獲得黏性黃色固體 之1-(4-(3-(3-氯-4-異丙氧基苯基）4,2,4-噚二唑·5_基）苯基） 環丙烷甲醛（144毫克，48%)。LCMS(表1，方法c) Rt=3.11 min? m/z 383.50 (M+H)+ ° 實例編號43 : 3-((1-(4-(3-(3-氣-4-異丙氧基苯基）4,2,4-崎 二唑基）苯基）環丙基）甲基胺基）丙酸，三氟己酸之製備Feed into a 100 ml round bottom bottle and then cool to -40 °C. DIBAL-H (0.869 mL, 0.869 mmol) was slowly added via a syringe and the mixture was allowed to warm to room temperature overnight. The reaction was quenched by the addition of Me 〇H (4 mL) and EtOAc (4 mL). The layers were separated and the aqueous layer was extracted with DCM (3.times.25 mL). The organic layer was washed with a saturated sodium bicarbonate solution, then dehydrated with EtOAc and concentrated. 3 ml of 1N HCl was added to a solution of the crude material in 3 ml of THF. The mixture was stirred at room temperature for 1 hour. The mixture was subjected to rotary evaporation to remove THF. This material was then subjected to flash column chromatography (Anal 〇gix, 4 gram column, 0-40% ethyl acetate / heptane for 3 Torr, flow rate 3 〇 cc / min). The product-containing fractions were combined and concentrated to give 1-(4-(3-(3-chloro-4-isopropoxyphenyl)4,2,4-oxadiazole·5_ Base) phenyl) cyclopropanecarbaldehyde (144 mg, 48%). LCMS (Table 1, Method c) Rt = 3.11 min? m/z 383.50 (M+H) + ° Example No. 43: 3-((1-(4-(3-(3-)) Preparation of phenyl) 4,2,4-oxadiazolyl)phenyl)cyclopropyl)methylamino)propionic acid, trifluorohexanoic acid

將1-(4-(3-(3-氯-4-異丙氧基苯基，仁嘮二唑基）苯 基）環丙烷甲醛（46毫克，0.120毫莫耳）、曱醇（2·5毫升）、 3-胺基丙酸（10.70¾克，〇·12〇毫莫耳）及乙酸（〇〇34毫升， 0.601¾莫耳）饋入20毫升藥瓶中。將藥瓶蓋住且使混合物 在室溫下㈣約3G分鐘。接著添加_份氰基氫化納（7·55 耄克，0.1 20¾莫耳）且使反應在室溫下攪拌隔夜。減壓移 127788.doc -176· 200840567 除溶劑且使粗製物質經RP-HPLC(A=0.1% TFA，B=ACN ; 30%至95% B，以21·0毫升/分鐘歷時30分鐘；υνλ=254 nm; Thermo Hyperprep HS C18，8 μπι，250x21.2 mm管柱）純 化。使含產物之溶離份經旋轉蒸發並經凍乾，獲得3-((1-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-哼二唑-5-基）苯基）環丙 基）甲基胺基）丙酸（27毫克，40%)之TFA鹽。LCMS(表1， 方法 c) Rt=2.07 min，m/z 456.25 (M+H)+;NMR (400 MHz，曱醇）J ppm 8·22 (d，2H)，8.11 (d，1H)，8·03 (dd，1H)， 7.69 (d，《7=8.19 Hz，2H)，7.24 (d，1H)，4.80-4.76 (m，1H)， 3.36 (s5 2H)，3.13 (t，，2H)，2.44 (t，2H)，1.40 (d，6H)，1.17 (d，4H) ° 實例編號44 : N-(4-(3-(3-氣-4-異丙氧基苯基）-12,4-噚二 唑基）苄基）-1-(2,2·二甲基-i，3-二氧雜環戊-4-基）甲烷胺 之製備1-(4-(3-(3-Chloro-4-isopropoxyphenyl), benzodiazolyl)phenyl)cyclopropanecarbaldehyde (46 mg, 0.120 mmol), decyl alcohol (2· 5 ml), 3-aminopropionic acid (10.703⁄4 g, 〇12〇 mmol) and acetic acid (〇〇34 ml, 0.6013⁄4 mol) were fed into a 20 ml vial. Cover the vial and The mixture was allowed to react at room temperature (iv) for about 3 G minutes. Then, _ part of sodium cyanohydride (7·55 gram, 0.1 203⁄4 mol) was added and the reaction was stirred at room temperature overnight. 127788.doc -176· 200840567 Solvent removal and crude material by RP-HPLC (A=0.1% TFA, B=ACN; 30% to 95% B, 21.0 ml/min for 30 minutes; υνλ=254 nm; Thermo Hyperprep HS C18, Purification of 8 μπι, 250×21.2 mm column. The product-containing fraction was subjected to rotary evaporation and lyophilized to obtain 3-((1-(4-(3-(3-chloro-4-isopropoxy)oxy). Phenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropyl)methylamino)propanoic acid (27 mg, 40%) of TFA salt. LCMS (Table 1, Method c Rt=2.07 min, m/z 456.25 (M+H)+; NMR (400 MHz, decyl alcohol) J ppm 8·22 (d, 2H), 8.11 (d, 1H), 8·03 (dd, 1H) ) 7.69 (d, "7=8.19 Hz, 2H), 7.24 (d, 1H), 4.80-4.76 (m, 1H), 3.36 (s5 2H), 3.13 (t,, 2H), 2.44 (t, 2H), 1.40 (d,6H), 1.17 (d,4H) ° Example No. 44: N-(4-(3-(3-Gas-4-isopropoxyphenyl)-12,4-oxadiazolyl) Preparation of benzyl)-1-(2,2·dimethyl-i,3-dioxol-4-yl)methaneamine

將4-(3-(3-氣-4-異丙氧基苯基）-；1，2,4^号二唑巧_基）苯曱4-(3-(3-Gas-4-isopropoxyphenyl)-; 1,2,4^dicarbazide phenyl)

合物在室溫下攪拌隔夜 乞’ 0.438毫莫耳），且使反應混 減壓移除溶劑且使粗製物質經 127788.doc -177- 200840567 RP-HPLC(A=50 mM 乙酸銨；B=ACN ; 40%至 80%B歷時 30 分鐘，21.0 毫升/分鐘，UV λ=254 nm; Thermo Hyperprep HS C18，8 μπι，250x21.2 mm管柱）純化。合併含產物之溶 離份，經旋轉蒸發及凍乾，獲得白色固體之N-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-呤二唑-5-基）苄基）-1-(2,2-二甲基-1，3- —氧雜環戊-4-基）甲烧胺（130.9毫克，64.7%)。 LCMS(表 1，方法c) Rt=2.59 min，m/z 458.62 (M+H)+; NMR (400 MHz，DMSO) δ ppm 8·13 (d，2H)，8·06 (d，1H)， 8.00 (dd，1H)，7.61 (d，2H)，7.39 (d，1H)，4.82 (sept，1H)， 4·15 (p，1H)，3.99 (dd，1H)，3.84 (s，2H)，3·63 (dd，1H)， 2.61 (ddd，2H)，1·86 (s，4H)，1.35 (d，6H) 1.26 (s，3H)。 實例編號45 : 3-(4-(3-(3-氣-4-異丙氧基苯基）-ΐ，2,4·噚二 唑-5-基）节基胺基）丙烷β1，2_二醇之製備The mixture was stirred overnight at room temperature 0.4 0.438 mmol, and the reaction was combined with reduced pressure to remove solvent and the crude material was subjected to 127788.doc -177 - 200840567 RP-HPLC (A = 50 mM ammonium acetate; B = ACN; 40% to 80% B for 30 minutes, 21.0 ml/min, UV λ = 254 nm; Thermo Hyperprep HS C18, 8 μπι, 250 x 21.2 mm column). The product-containing fractions were combined and evaporated to dryness to give N-(4-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole as a white solid. -5-yl)benzyl)-1-(2,2-dimethyl-1,3-oxocyclo-4-yl)metholamine (130.9 mg, 64.7%). LCMS (Table 1, Method c) Rt=2.59 min, m/z 458.62 (M+H)+; NMR (400 MHz, DMSO) δ ppm 8·13 (d,2H),8·06 (d,1H) , 8.00 (dd, 1H), 7.61 (d, 2H), 7.39 (d, 1H), 4.82 (sept, 1H), 4·15 (p, 1H), 3.99 (dd, 1H), 3.84 (s, 2H) ), 3·63 (dd, 1H), 2.61 (ddd, 2H), 1·86 (s, 4H), 1.35 (d, 6H) 1.26 (s, 3H). Example No. 45: 3-(4-(3-(3-Ga-4-isopropoxyphenyl)-indole, 2,4·oxadiazol-5-yl)-benzylamino)propane β1,2 Preparation of diol

於含Ν_(4-(3-(3ϋ異丙氧基苯基）-1，2,4-。号二唑-5-基） 节基）-1·(2,2-二甲基-1&gt;3_二氧雜環戊-扣基）甲烷胺（1〇8毫 克’ 〇·236毫莫耳）之THF(4毫升）溶液中添加1 N HC1水溶液 (0.778毫升’ 〇·778毫莫耳）。使反應在氮氣中加熱至65。〇 歷時90分鐘。停止加熱且添加1 ν NaOH水溶液（0·778毫 升’ 〇.778毫莫耳）中和反應。減壓移除THF且添加0.1 Ν Na〇H使剩餘水溶液鹼化（pH約9)，此時形成白色沉澱物。 真空過濾收集固體且以〇·1Ν NaOH(3xlO毫升）洗滌。固體 127788.doc -178- 200840567 於真空烘箱中乾燥隔夜，獲得灰白色固體之3-(4-(3-(3-氯-4-異丙氧基苯基）-i，2,4-噚二唑-5-基）苄基胺基）丙烷-i，2-二 醇（31 ·7毫克，32%)。LCMS(表 1，方法c) Rt=l.90 min，m/z 418·47 (M+H)+;NMR (400 MHz，甲醇；δ ppm 7·22 (d， &gt;8·68 Hz，1H)，7·60 (d，2H)，8.01 (dd，，1H)，8.10 (d，1H)， 8.16 (d，2H)，4.78 (sept，1H)，2.76 (dd，1H)，2·63 (dd，1H)， 3.52 (d，2H)，3.90 (d，2H)，3.78 (m，1H)，1.40 (d，6H)。 實例編號46 : 3-(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-噚二 峡-5-基）苯基）丙烯酸（Z)-甲酯之製備Containing Ν_(4-(3-(3ϋisopropoxyphenyl)-1,2,4-.diazol-5-yl)))-1(2,2-dimethyl-1) Add 3 N HCl solution (0.778 ml '〇·778 mmol) to a solution of 3_dioxol-methyl)methaneamine (1〇8 mg '〇·236 mmol) in THF (4 ml) ). The reaction was heated to 65 under nitrogen.历 Lasted 90 minutes. The heating was stopped and a 1 ν aqueous solution of NaOH (0·778 ml ’. 778 mmol) was added to neutralize the reaction. The THF was removed under reduced pressure and 0.1 Ν Na 〇 H was added to basify the remaining aqueous solution (pH about 9), at which time a white precipitate formed. The solid was collected by vacuum filtration and washed with EtOAc (EtOAc). Solid 127788.doc -178- 200840567 was dried overnight in a vacuum oven to give 3-(4-(3-chloro-4-isopropoxyphenyl)-i,2,4-indole as an off-white solid. Zyrid-5-yl)benzylamino)propane-i,2-diol (31 · 7 mg, 32%). LCMS (Table 1, Method c) Rt = 1.90 min, m/z 418. 47 (M+H)+; NMR (400 MHz, methanol; δ ppm 7.22 (d, &gt;8·68 Hz, 1H),7·60 (d,2H), 8.01 (dd,,1H), 8.10 (d,1H), 8.16 (d,2H), 4.78 (sept,1H), 2.76 (dd,1H),2· 63 (dd,1H), 3.52 (d,2H), 3.90 (d,2H), 3.78 (m,1H), 1.40 (d,6H). Example No. 46: 3-(4-(3-(3- Preparation of (Z)-methyl ester of gas-4-isopropoxyphenyl)-1,2,4-anthraquinone-5-yl)phenyl)acrylic acid

於二頸圓底瓶中饋入2-(雙（2,2,2-三氟乙氧基）磷醯基）乙 酸甲醋（0.235毫升，1.109毫莫耳）、18-冠狀醚-6(1465毫 克’ 5.54毫莫耳）及THF(15毫升）。接著使混合物在氮氣中 冷卻至-78°C。添加雙（三曱基矽烷基）醯胺鉀（221亳克， L109*莫耳）且使混合物攪拌數分鐘。添加4-(3-(3-氣-4-異 丙氧基苯基）-1，2,4-噚二唑-5-基）苯甲醛（380毫克，1.109毫 莫耳）並使混合物在-78°C下攪拌90分鐘且接著使之升溫至 至概仪。添加飽和NH4C1(水溶液）終止反應。分離混合 物且以乙醚（3x10毫升）萃取水層。合併之有機層RMgS〇4 脫水並濃縮’獲得灰白色固體。以Me〇H研散該固體且真 空過濾收集，並以MeOH(3xl〇毫升）洗滌。收集之固體經 真空烘箱乾燥，獲得3-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4- I27788.doc 179- 200840567 哼二唑-5-基）苯基）丙烯酸甲酯（325毫克，73·5%)。 LCMS(表 1，方法c) Rt=3.22 min，m/z 399.16 (Μ+Η)+。 NMR (400 ΜΗζ，DMSO) δ ppm 8·18 (d，2Η)，8·06 (d，1Η)， 8·01 (dd，1Η)，7·79 (d，2Η)，7·40 (d，1Η)，7·18 (d，1Η)，6.84 (d，1Η)，6·20 (d，1Η)，4.83 (sept，1Η)，3.67 (s，3Η)，1·35 (d， 6Η) 〇 實例編號47 : 2-(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-噚二 峻-5_基）苯基）環丙烧甲酸反式·甲酯之製備2-(bis(2,2,2-trifluoroethoxy)phosphonium)acetic acid methyl vinegar (0.235 ml, 1.109 mmol) and 18-crown ether-6 were fed into a two-neck round bottom flask. 1465 mg ' 5.54 mmoles) and THF (15 ml). The mixture was then cooled to -78 ° C under nitrogen. Bis(tridecyldecylalkyl)guanamine potassium (221 g, L109* mole) was added and the mixture was allowed to stir for a few minutes. 4-(3-(3-Gas-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (380 mg, 1.109 mmol) was added and the mixture was Stir at -78 ° C for 90 minutes and then warm to the instrument. The reaction was terminated by the addition of saturated NH4C1 (aq.). The mixture was separated and the aqueous extracted with diethyl ether (3×10 mL). The combined organic layers RMgS 〇 4 were dehydrated and concentrated to afford an off white solid. The solid was triturated with Me 〇 H and collected by vacuum filtration and washed with MeOH (3.times. The collected solid was dried in a vacuum oven to give 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-I27788.doc 179-200840567 oxadiazole-5- Methyl) phenyl) acrylate (325 mg, 73.5%). LCMS (Table 1, Method c) Rt = 3.22 min, m/z 399.16 ( Μ + Η) +. NMR (400 ΜΗζ, DMSO) δ ppm 8·18 (d, 2Η), 8·06 (d, 1Η), 8·01 (dd, 1Η), 7·79 (d, 2Η), 7·40 (d ,1Η),7·18 (d,1Η), 6.84 (d,1Η),6·20 (d,1Η),4.83 (sept,1Η), 3.67 (s,3Η),1·35 (d, 6Η) 〇Example No. 47: 2-(4-(3-(3-Gas-4-isopropoxyphenyl)-1,2,4-anthracene-5-yl)phenyl) propylpropenate Preparation of trans-methyl ester

在氮氣中於含三曱基亞砜鏽碘（234毫克，1.065毫莫耳） 之DMSO(5.0毫升）攪拌懸浮液中一次添加NaH(42.6毫克， 1·〇65毫莫耳），且搭配水浴使反應維持在25-3〇°c之間。氫 氣完全釋出後’使反應溫度維持在35°c或低於35°c之下滴 加含3-(4-(3-(3•氯-4-異丙氧基苯基）_ι，2,4-嘮二唑-5-基）苯 基）丙烯酸（Z)-甲酯（386毫克，0.968毫莫耳）之DMSO(5.00 笔升）溶液。添加完成後，使反應在室溫下擾拌一個半小 時，接著使之升溫至5(TC歷時二小時。接著於反應中添加 50宅升之水’且使反應在室溫下攪拌隔夜。反應混合物以 飽和氯化鈉水溶液稀釋，且以3x75毫升EtOAc萃取水層。 石併有機層’以MgS〇4脫水並濃縮。粗製物質經Rp·Add NaH (42.6 mg, 1·〇65 mmol) in a stirred suspension of DMSO (5.0 mL) containing trimethylsulfoxide rust iodine (234 mg, 1.065 mmol) in a nitrogen bath with water bath The reaction was maintained between 25 and 3 °C. After the hydrogen is completely released, the reaction temperature is maintained at 35 ° C or below 35 ° C, and 3-(4-(3-(3•chloro-4-isopropoxyphenyl)_ι, 2 is added dropwise. a solution of (Z)-methyl ester (4- oxazol-5-yl)phenyl) acrylate (386 mg, 0.968 mmol) in DMSO (5.00 L). After the addition was completed, the reaction was allowed to stir at room temperature for one and a half hours, then allowed to warm to 5 (TC for two hours. Then 50 liters of water was added to the reaction) and the reaction was allowed to stir at room temperature overnight. The mixture was diluted with a saturated aqueous solution of sodium chloride and aqueous layer was extracted with &lt;RTI ID=0.0&gt;&gt;

HPLC(A=50 mM 乙酸銨；B=ACN ; 30%至 1〇〇%Β歷時 30分 、’里 21 .〇毫升/分鐘 ’ UV nm; Thermo Hyperprep HS 127788.doc •180- 200840567 C18，8 μπι，250x21.2 mm管柱）純化。合併含產物之溶離 份，經濃縮及凍乾，獲得白色固體之2-(4-(3-(3-氯-4-異丙 氧基苯基）-1，2,4-吟二唑-5-基）苯基）環丙烷甲酸反式-甲酯 (155毫克，39%)。LCMS(表 1，方法 c) R严3·27 min，m/z 413·17 (M+H)+。NMR (400 MHz，DMSO) δ ppm 8.08 (d， 2H)，8.06 (d，1H)，7·99 ( dd，1H)，7.47 (d，2H)，7.39 (d， 1H)，4·82 (sept，1H)，3.66 (s，3H)，2.59 (ddd，1H)，2.12 (ddd，1H)，1·58 (ddd，1H)，1·53 (ddd，1H)，1·35 (d，6H)。 實例編號48·反式-2-(4-(3_(3_氯-4_異丙氧基苯基）-ΐ，2,4· 噚二唑基）苯基）環丙烷甲酸之製備HPLC (A = 50 mM ammonium acetate; B = ACN; 30% to 1% hydrazine for 30 minutes, 'Li 21 〇 ml / min' UV nm; Thermo Hyperprep HS 127788.doc • 180- 200840567 C18,8 Purified by μπι, 250 x 21.2 mm column. The product-containing fractions were combined, concentrated and lyophilized to give 2-(4-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole as a white solid. 5-Methyl)phenyl)cyclopropanecarboxylic acid trans-methyl ester (155 mg, 39%). LCMS (Table 1, Method c) R: 3.27 min, m/z 413·17 (M+H)+. NMR (400 MHz, DMSO) δ ppm 8.08 (d, 2H), 8.06 (d, 1H), 7·99 ( dd, 1H), 7.47 (d, 2H), 7.39 (d, 1H), 4·82 ( Sept,1H), 3.66 (s,3H), 2.59 (ddd,1H), 2.12 (ddd,1H),1·58 (ddd,1H),1·53 (ddd,1H),1·35 (d, 6H). Example No. 48. Preparation of trans-2-(4-(3_(3_chloro-4_isopropoxyphenyl)-indole, 2,4·oxadiazolyl)phenyl)cyclopropanecarboxylic acid

於含2-(4-(3-(3-氣-4-異丙氧基苯基丨又扣嘮二唑-5-基） 苯基)環丙烷甲酸（1S，2S)-甲酯（hi毫克，〇·269毫莫耳）之 乙醇（5毫升）懸浮液中添加2 N NaOH(5毫升，10.00毫莫 耳）。使混合物在室溫下及氮氣中攪拌隔夜。添加乙酸中 和反應混合物，且接著以數滴1 N HC1水溶液酸化（pH約 2)。過濾收集白色固態沉澱物，以〇·ι n HCl(3x5毫升）洗 滌並經真空乾燥’獲得反式_2-(4_(3-(3-氯-4_異丙氧基苯 基）-1，2,4-噚二唑-5-基）苯基）環丙烷甲酸（64毫克，59%)。 LCMS(表 1，方法F) Rt=2.99 min，m/z 399·16 (M+H)+。 NMR (400 MHz，DMSO) δ ppm 8.07 (d，2H)，8·05 (d，1H)， 7.99 (dd，1H)，7·45 (d，2H)，7·38 (d，1H)，4·82 (sept·，1H)， 127788.doc -181 - 200840567 2·54 (m，1Η)，1·97 (m，1Η)，1·53 (td，1Η)，1·46 (ddd，lH) 1.35 (d, 6H)。 實例編號49 : 5-(3-(3•氣-4-異丙氧基苯基呤二唑j 基）異吲哚啉-2-甲酸第三丁酯之製備Containing 2-(4-(3-(3- gas-4-isopropoxyphenylindole) oxazol-5-yl)phenyl)cyclopropanecarboxylic acid (1S,2S)-methyl ester (hi Add 2 N NaOH (5 mL, 10.00 mmol) to a suspension of ethanol (5 mL) in MeOH (2 mL). The mixture was stirred overnight at room temperature under nitrogen. And then acidified with a few drops of 1 N HCl aqueous solution (pH about 2). A white solid precipitate was collected by filtration, washed with 〇·ι n HCl (3×5 mL) and dried in vacuo to obtain trans _2-(4_(3) -(3-Chloro-4_isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarboxylic acid (64 mg, 59%). F) Rt=2.99 min, m/z 399·16 (M+H)+ NMR (400 MHz, DMSO) δ ppm 8.07 (d, 2H), 8.05 (d, 1H), 7.99 (dd, 1H) ),7·45 (d,2H),7·38 (d,1H),4·82 (sept·,1H), 127788.doc -181 - 200840567 2·54 (m,1Η),1·97 ( m,1Η),1·53 (td,1Η),1·46 (ddd,lH) 1.35 (d, 6H). Example No. 49: 5-(3-(3•gas-4-isopropoxybenzene) Base oxadiazole j-based) isobutyl porphyrin-2-carboxylic acid tert-butyl ester Equipment

在5毫升微波藥瓶中，於含2-(第三丁氧基羰基）異。引。朵 琳-5-甲酸（190¾克’ 0.722毫莫耳）之乙腈（3毫升）溶液中添 加HOBT(330毫克，2.16毫莫耳）、DCC(298毫克，2 16毫莫 耳）及DIEA(0.115毫升，0.656毫莫耳）。使混合物在室溫下 攪拌約16小時。接著，添加（Z)-3-氣-N，-羥基-4-異丙氧基 苯甲脒（150毫克，0.65 6毫莫耳）（以通用程序b製備），且使 反應在微波輻射（最大300 W)加熱至150°C歷時20分鐘。冷 卻後，過濾反應混合物，經濃縮且以Analogix系統，使用In a 5 ml microwave vial, it contains 2-(t-butoxycarbonyl). lead. Add DOBT (330 mg, 2.16 mmol), DCC (298 mg, 2 16 mmol) and DIEA (0.115) to a solution of Dolly-5-carboxylic acid (1903⁄4 g '0.722 mmol) in acetonitrile (3 mL). Kilograms, 0.656 millimoles). The mixture was stirred at room temperature for about 16 hours. Next, (Z)-3-gas-N,-hydroxy-4-isopropoxybenzamide (150 mg, 0.65 6 mmol) (prepared by the general procedure b) was added, and the reaction was allowed to undergo microwave irradiation ( Up to 300 W) heated to 150 ° C for 20 minutes. After cooling, the reaction mixture was filtered, concentrated and used in an Analogix system.

RediSep 40 g管柱，配合〇_40% EtOAc/庚烷之梯度在30毫RediSep 40 g column with a gradient of 〇40% EtOAc/heptane at 30 mM

升/分鐘流速下歷時3 0分鐘純化。合併含產物之溶離份， 經旋轉蒸發且以真空烘箱乾燥，獲得5-(3-(3-氯-4-異丙氧 基苯基）-1，2,4·呤二唑-5-基）異吲哚啉-2-甲酸第三丁酯（46.2 宅克 ’ 15,5%)。LCMS(表 1，方法 c) Rt=3.40 min，m/z 456.22 (M+H)+;NMR (400 MHz，DMSO) δ ppm 8.16 (d， 1H)，8.10 (s，1H)，8·〇5 (d，1H)，7·61 (m，1H)，7.39 (d，1H)， 4·82 (sept，1H)，4.70 (d，4H)，1.48 (s，9H)，1.35 (d，6H)。 實例編號50 : 3-(3-氣-4_異丙氧基苯基）-5-(異吲哚啉-5- 127788.doc -182- 200840567 基）-1，2,4-噚二唑，三氟乙酸之製備Purification was carried out for 30 minutes at a liter/min flow rate. The product-containing fractions were combined, rotary evaporated and dried in a vacuum oven to give 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4·oxadiazol-5-yl. ) Isoindoline-2-carboxylic acid tert-butyl ester (46.2 Neck '15, 5%). LCMS (Table 1, Method c) Rt = 3.40 min, m/z 456.22 (M+H)+; NMR (400 MHz, DMSO) δ ppm 8.16 (d, 1H), 8.10 (s,1H),8·〇 5 (d,1H),7·61 (m,1H),7.39 (d,1H), 4·82 (sept,1H), 4.70 (d,4H), 1.48 (s,9H), 1.35 (d, 6H). Example No. 50: 3-(3-Gas-4-isopropoxyphenyl)-5-(isoindoline-5-127788.doc-182-200840567)-1,2,4-oxadiazole , preparation of trifluoroacetic acid

於含5-(3-(3-氣-4-異丙氧基苯基）-1，2,4^号二唑基）異 吲哚啉-2-甲酸第三丁酯（41毫克，〇〇9〇毫莫耳）iDcM(2 耄升）溶液中添加TFA(0.5毫升，6·49毫莫耳）。使混合物在 室溫下及氮氣中攪拌約30分鐘。30分鐘後，將乙醚緩慢添 加於混合物中’直到變渾濁且形成白色沉澱物為止。過渡 收集固體且以乙醚（3xl〇毫升）洗滌。接著使收集之固體於 真工烘相中乾燥，獲得3-(3-氯-4-異丙氧基苯基）_$_(異叫丨 口朵琳-5-基）-1，2,4-呤二唑之 TFA 鹽（26·7 毫克，62.6%)。 LCMS(表1，方法c) Rt=2.29 min，m/z 356.17 (Μ+Η)+。 NMR (400 ΜΗζ，DMSO) δ ppm 9·46 (s，2Η)，8.27 (s，1Η) 8.20 (d，1Η)，8,00 (d，1Η)，7·70 (d，1Η)，7·41 (d，1Η)，4·83 (sept，1Η)，4·64 (d，4Η)，1.35 (d，6Η)。 實例編號51 : 3-(5-(3-(3-氣-4-異丙氧基苯基）4,2,1呤二 峻基）異吲哚啉-2-基）丙酸甲酯之製備Tetrabutyl ketone containing 5-(3-(3-, 4-isopropoxyphenyl)-1,2,4^diazolyl)isoindoline-2-carboxylic acid (41 mg, hydrazine) 〇 9 〇 millimolar) iDcM (2 liters) solution was added TFA (0.5 ml, 6. 49 mmol). The mixture was stirred at room temperature under nitrogen for about 30 minutes. After 30 minutes, ether was slowly added to the mixture until it became cloudy and a white precipitate formed. The solid was collected by chromatography and washed with diethyl ether (3.times. The collected solid is then dried in a solid bake phase to obtain 3-(3-chloro-4-isopropoxyphenyl)_$_ (also called 丨口朵琳琳-5-yl)-1,2, TFA salt of 4-oxadiazole (26·7 mg, 62.6%). LCMS (Table 1, Method c) Rt = 2.29 min, m/z 356.17 ( Μ + Η) +. NMR (400 ΜΗζ, DMSO) δ ppm 9·46 (s, 2Η), 8.27 (s, 1Η) 8.20 (d, 1Η), 8,00 (d, 1Η), 7·70 (d, 1Η), 7 · 41 (d, 1Η), 4·83 (sept, 1Η), 4·64 (d, 4Η), 1.35 (d, 6Η). Example No. 51: 3-(5-(3-(3-Ga-4-isopropoxyphenyl)4,2,1 fluorenyl)isoindoline-2-yl)methyl propionate preparation

將3-(3-氯-4-異丙氧基苯基）-5-(異吲哚啉_5_基，‘吟 二唑（16·7毫克，0.047毫莫耳）添加於裝置有攪拌棒之2毫 升微波藥瓶中。添加丙烯酸甲酯（8·45微升，〇 〇94毫莫耳） 127788.doc -183- 200840567 及甲醇（1.0¾升），盍住藥瓶，以微波輻射（3〇〇w)將反應嘉 熱至90 C歷時20分鐘。20分鐘後，添加另一份丙烯酸甲酯 (8·45微升，0·094毫莫耳），再將藥瓶密封，且以微波輻射 (300W)加熱至11〇。(：歷時40分鐘。接著濃縮反應且以真空 乾综隔夜，獲得粗製黃色油之3彳5_(3气弘氯_4_異丙氧基苯 基）-1，2,4-喝二唑-5 -基）異吲哚啉_2_基）丙酸甲酯（21 ·6毫 克，104%)。該產物未經進一步純化使用。lcMS(表1，方 法 c) Rt=2.85 min，w/z 442.45 (Μ+Η)+。 實例編號S2 : 3-(5-(3-(3-氣異丙氧基苯基号二 峻·5_基）異*5丨嗓淋-2-基）丙酸，鹽酸之製備Add 3-(3-chloro-4-isopropoxyphenyl)-5-(isoporphyrin-5-yl, 'oxadiazole (16·7 mg, 0.047 mmol) to the device with stirring In a 2 ml microwave vial, add methyl acrylate (8·45 μl, 〇〇94 mmol) 127788.doc -183- 200840567 and methanol (1.03⁄4 liter), hold the vial, microwave radiation (3〇〇w) The reaction was heated to 90 C for 20 minutes. After 20 minutes, another portion of methyl acrylate (8·45 μl, 0·094 mmol) was added, and the vial was sealed, and It was heated to 11 Torr by microwave irradiation (300 W). (: 40 minutes. Then the reaction was concentrated and dried overnight in vacuo to obtain a crude yellow oil of 3 彳 5 _ (3 gas chlorinated 4- 4 isopropyloxyphenyl) -1,2,4-dioxazol-5-yl)isoindoline-2-yl)propionic acid methyl ester (21 · 6 mg, 104%). This product was used without further purification. lcMS (Table 1, Method c) Rt = 2.85 min, w/z 442.45 (Μ + Η) +. Example No. S2: Preparation of 3-(5-(3-(3-oxaisopropoxyphenyl) succinyl-5-yl)iso*5-indole-2-yl)propionic acid, hydrochloric acid

於含3-(5-(3-(3-氣-4-異丙氧基苯基）-i,2，4-ρ号二。坐_5-基） 異吲哚啉-2-基）丙酸甲酯（21毫克，0.048毫莫耳）之乙醇（J 毫升）溶液中添加2M NaOH水溶液（1毫升，2·〇〇〇毫莫耳）。 使反應在室溫下及氮氣中攪拌約4小時。接著添加2N HC1 使反應混合物酸化至PH1，此時形成沉澱物。過濾收集固 體且以水（3x5毫升）洗滌。於真空烘箱中使固體乾燥隔夜， 獲付3-(5-(3-(3 -氣-4 -異丙氧基苯基）-i，2,4-p号二σ坐基）異 吲哚啉-2-基）丙酸之鹽酸鹽（ι〇·2毫克，46.2%)。LCMS(表 1，方法c) Rt=1.86 min，m/z 428.20 (Μ+Η).。h NMR (400 MHz，DMSO) δ ppm 12.12 (m，1H)，8·23 (s，1H)，8.19 (d 1H)，8·07 (d，1H)，8.01 (dd，1H)，7·68 (d，1H)，7.41 (d，1H)， 127788.doc -184- 200840567 4·83 (七重峰，1H)，4.72 (s，4H)，3·58 (t，2H)，2.84 (t，2H)， 1.36 (d，6H) 〇 實例編號53 : 3-(4-(3-(3-氯_4·異丙氧基苯基）4,2,4-吟二 唑基）苯基）丙烯酸（Z)-甲酯之製備Containing 3-(5-(3-(3-carb-4-isopropoxyphenyl)-i, 2,4-p. II.sodium-5-yl)isoindoline-2-yl) A solution of methyl propionate (21 mg, 0.048 mmol) in ethanol (J mL) was added 2M aqueous NaOH (1 mL, EtOAc). The reaction was allowed to stir at room temperature under nitrogen for about 4 hours. The reaction mixture was then acidified to pH 1 with the addition of 2N HCl, at which time a precipitate formed. The solid was collected by filtration and washed with water (3×5 mL). The solid was dried overnight in a vacuum oven to give 3-(5-(3-(3-(3-(4-(4-)-isopropoxyphenyl)-i, 2,4-p) Hydrochloride-2-phenyl)propionic acid hydrochloride (m. 2 mg, 46.2%). LCMS (Table 1, Method c) Rt = 1.86 min, m/z 428.20 (Μ+Η). h NMR (400 MHz, DMSO) δ ppm 12.12 (m, 1H), 8.23 (s, 1H), 8.19 (d 1H), 8.07 (d, 1H), 8.01 (dd, 1H), 7· 68 (d,1H), 7.41 (d,1H), 127788.doc -184- 200840567 4·83 (seven peaks, 1H), 4.72 (s,4H),3·58 (t,2H), 2.84 (t ,2H), 1.36 (d,6H) 〇Example No. 53 : 3-(4-(3-(3-Chloro-4)isopropoxyphenyl)4,2,4-oxadiazolyl)phenyl Preparation of acrylic acid (Z)-methyl ester

以2-(雙（2,2,2-三氟乙氧基）磷醯基）乙酸曱酯（〇·235毫 升，1，109毫莫耳）、18-冠狀醚-6(1465毫克，5.54毫莫耳） 及THF(15毫升）饋入二頸圓底瓶中。在氮氣中使混合物冷 钟至-78 °C。添加雙（三甲基石夕燒基）醯胺_ (221毫克， 1109毫莫耳）且使混合物攪拌數分鐘。添加4_(3-(3_氣-4_異 丙氧基苯基）-1，2,4-噚二唑-5-基）苯曱醛（380毫克，ι.1〇9毫 莫耳）且使混合物在-78°C下攪拌90分鐘，且接著使之升溫 至室溫隔夜。添加飽和NHjCl(水溶液）終止反應。分離混 合物且以乙醚（3x10毫升）萃取水層。合併之有機層以 MgSCU脫水並濃縮，獲得灰白色固體。以Me〇H研散該固 體且真空過濾收集，並以MeOH(3xl〇毫升）洗務。使收集 之固體於真空烘箱中乾燥隔夜，獲得3-(4-(3-(3-氯-4-異丙 氧基苯基）-1，2，本噚二唑-5-基）苯基）丙烯酸（z)_曱酯（325毫 克 ’ 73.5%)。LCMS(表 1，方法c) Rt=3.22 min，m/z 399·16 (Μ+Η)+。NMR (400 ΜΗζ，DMSO) δ ppm 8·18 (d，2Η)， 8·06 (d，1Η)，8·01 (dd，1Η)，7·79 (d，2Η)，7·40 (d，1Η)，7·18 (d，1H)，6·84 (d，1H)，6·20 (d，1H)，4·83 (sept，1H)，3.67 (s， 127 788.doc -185- 200840567 3H)，1·35 (d，6H) 〇 實例編號54 ·· (Ζ)-3-(4-(3-(3-氣-4-異丙氧基苯基号 二嗤基）苯基）丙稀酸之製備Ethyl 2-(bis(2,2,2-trifluoroethoxy)phosphonium) acetate (〇·235 ml, 1,109 mmol), 18-crown-6 (1465 mg, 5.54) Millol) and THF (15 ml) were fed into a two-neck round bottom bottle. The mixture was chilled to -78 °C under nitrogen. Bis(trimethyl-stone) guanamine _ (221 mg, 1109 mmol) was added and the mixture was stirred for a few minutes. Add 4_(3-(3_gas-4_isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylfurfural (380 mg, ι.1〇9 mmol) The mixture was stirred at -78 °C for 90 minutes and then allowed to warm to room temperature overnight. The reaction was stopped by the addition of saturated NHjCl (aqueous solution). The mixture was separated and the aqueous extracted with diethyl ether (3×10 mL). The combined organic layers were dried over MgSCU and concentrated to give a white solid. The solid was triturated with Me〇H and collected by vacuum filtration and washed with MeOH (3.times. The collected solid was dried overnight in a vacuum oven to give 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2, oxadiazole-5-yl)phenyl. ) (z)-decyl acrylate (325 mg '73.5%). LCMS (Table 1, Method c) Rt = 3.22 min, m/z 399.16 ( Μ + Η) +. NMR (400 ΜΗζ, DMSO) δ ppm 8·18 (d, 2Η), 8·06 (d, 1Η), 8·01 (dd, 1Η), 7·79 (d, 2Η), 7·40 (d ,1Η),7·18 (d,1H),6·84 (d,1H),6·20 (d,1H),4·83 (sept,1H),3.67 (s, 127 788.doc -185 - 200840567 3H),1·35 (d,6H) 〇Example No. 54 ··(Ζ)-3-(4-(3-(3-Ga-4-isopropoxyphenyl)diphenyl)benzene Base) preparation of acrylic acid

於含3-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-噚二唑_5-基） 苯基）丙烯酸（Z)-曱酯（30毫克，0,075毫莫耳）之EtOH(2毫 升）溶液中添加2 N NaOH水溶液（2毫升）。使反應在室溫下 及氮氣中攪拌2小時。添加1 N HC1使反應酸化直到形成沉 澱物。過濾收集固體，以〇·2 N HC1洗滌且於真空烘箱中乾 燥，獲得（Ζ)-3-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-嘮二唑-5_基）笨基）丙烯酸（8.2毫克，28.3%)。LCMS(表1，方法c) Rt:=2.64 min5 m/z 385.12 (M+H)+. lH NMR (400 MHz, DMSO) δ ppm 13.11-12.20 (m，1H)，8.15 (d，2H)，8.04 (d， 1H)，7·99 (dd，，1H)，7.78 (d，2H)，7.37 (d，1H)，7.03 (d， 1H)，6·12 (d，1H)，4·81 ( sept·，1H)，1.33 (d，6H)。 實例編號55 : 3-氣-4-(3-(3-氣異丙氧基苯基）·1，2,4-噚二 唑-5-基）苯胺之製備(Z)-decyl ester containing 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole-5-yl)phenyl)acrylate A solution of 2 N NaOH (2 mL) was added to a solution of EtOAc (2 mL). The reaction was allowed to stir at room temperature under nitrogen for 2 hours. The reaction was acidified by the addition of 1 N HCl until a precipitate formed. The solid was collected by filtration, washed with EtOAc EtOAc EtOAc (EtOAc) 4-oxadiazole-5-yl) stupid) acrylic acid (8.2 mg, 28.3%). LCMS (Table 1, Method c) Rt: = 2.64 min5 m/z 385.12 (M+H) +. lH NMR (400 MHz, DMSO) δ ppm 13.11-12.20 (m, 1H), 8.15 (d, 2H), 8.04 (d, 1H), 7·99 (dd,, 1H), 7.78 (d, 2H), 7.37 (d, 1H), 7.03 (d, 1H), 6·12 (d, 1H), 4·81 (sept·, 1H), 1.33 (d, 6H). Example No. 55: Preparation of 3-oxo-4-(3-(3-isopropoxyphenyl)·1,2,4-oxadiazol-5-yl)aniline

將（Ζ)-3-氯-Ν，-經基-4-異丙氧基苯甲腩（〇·5克’ 2.187毫 莫耳)、4-胺基-2-氯苯甲酸（〇·413克，2·405毫莫耳）、DCC 127788.doc • 186- 200840567 (0.496克，2.405 毫莫耳）、ΗΟΒΤ(0·368 克，2.405 毫莫耳)置 於80毫升微波藥瓶中，且添加乙腈（12.01毫升）。使反應混 合物在室溫下攪拌5分鐘，接著添加DIEA(0.840毫升， 4.81毫莫耳）。以微波將反應混合物加熱至120°C歷時30分 鐘。TLC (5 0% EA/庚烷）顯示 4點 Rf 0.8、0.6、0.5及 0·3。 以 UV顯示之LCMS(2007—9349)為 16% (2.61 mins)至（Μ+Η) 304.31 〇移除溶劑且使粗製物質經FCC(50% EA/庚烷）純 化’獲得3 -氣-4-( 3-(3 -氣-4-異丙氧基苯基）-1，2，4 -p亏二嗤-5 _ 基）苯胺（534毫克，1.466毫莫耳，產率67.1%)。LCMS(表 A，方法b)以UV顯示為99%(3·10分鐘），且以ELSD顯示為 92%(3.06分鐘）至（Μ+Η)+ 364.12。 實例編號56 : 3-(3-氯-4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-哼二唑-5-基）苯基胺基）環丁烷甲酸之製備(Ζ)-3-chloro-indole,-yl-4-isopropoxybenzamide (〇·5 g ' 2.187 mmol), 4-amino-2-chlorobenzoic acid (〇·413克, 2·405 millimoles), DCC 127788.doc • 186- 200840567 (0.496 g, 2.405 mM), ΗΟΒΤ (0·368 g, 2.405 mM) in an 80 ml microwave vial, and Acetonitrile (12.01 ml) was added. The reaction mixture was allowed to stir at room temperature for 5 min then DIEA (0.840 mL, 4.81 mmol). The reaction mixture was heated to 120 ° C with microwave for 30 minutes. TLC (50% EA/heptane) shows 4 points Rf 0.8, 0.6, 0.5 and 0·3. The LCMS (2007-9349) in UV is 16% (2.61 mins) to (Μ+Η) 304.31 〇The solvent is removed and the crude material is purified by FCC (50% EA/heptane) to obtain 3- gas-4 -( 3-(3-Gas-4-isopropoxyphenyl)-1,2,4-p-dioxa-5-yl)aniline (534 mg, 1.466 mmol, yield 67.1%). LCMS (Table A, Method b) was 99% (3·10 min) in UV and 92% (3.06 min) to (Μ+Η) + 364.12 as shown by ELSD. Example No. 56: 3-(3-Chloro-4-(3-(3-carb-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino) Preparation of cyclobutanecarboxylic acid

在室溫下於含3-氯_4-(3-(3-氯-4-異丙氧基苯基）-1，2,4-嘮 二唑-5-基）苯胺（200毫克，0.549毫莫耳）及3-側氧基環丁烷 甲酸（62.7毫克，0.549毫莫耳）之甲醇（1280微升）中添加乙 酸（842微升，14.72毫莫耳）。使反應混合物在室溫下攪拌 10分鐘，接著一次添加氰基硼氫化鈉（17.25毫克，0.275毫 莫耳）。使反應混合物在室溫下攪拌隔夜。LCMS (2007_9476)顯示由 ELSD(2.90 mins)有 43%轉化成（M+H) 462.16。移除溶劑且使粗製物質經FCC(50% EA/庚烷）純 127788.doc -187- 200840567 化，獲得白色固體之3-(3-氯-4-(3-(3-氯-4-異丙氧基笨基）_ 1，2,4-嘮二唑-5-基）苯基胺基）環丁烷甲酸（135毫克，0.292 毫莫耳，53.2%)。LCMS(表A，方法b)顯示藉UV(3.06 mins)偵測為 100%至（Μ+Η)+ 364.12。 製備例編號21 : 4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-噚二唑-5_基）苯胺3-Chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (200 mg, 0.549) at room temperature Acetic acid (842 μl, 14.72 mmol) was added to methanol (1280 μl) of mM o-oxycyclobutanecarboxylic acid (62.7 mg, 0.549 mmol). The reaction mixture was stirred at room temperature for 10 min then sodium cyanoborohydride (17.25 mg, 0.275 m. The reaction mixture was allowed to stir at room temperature overnight. LCMS (2007_9476) showed 43% conversion from ELSD (2.90 mins) to (M+H) 462.16. The solvent was removed and the crude material was purified EtOAc EtOAc EtOAc EtOAc EtOAc Isopropoxy phenyl)- 1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (135 mg, 0.292 mmol, 53.2%). LCMS (Table A, Method b) showed 100% to (Μ+Η)+ 364.12 by UV (3.06 mins). Preparation No. 21: 4-(3-(3-Gas-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline

於微波藥瓶中混合（Z)_3-氯-N、羥基_4_異丙氧基苯曱脒 (1克，4.37毫莫耳）、胺基苯甲酸（0,660克，4.81毫莫 耳）、ΗΟΒΤ(0·737克，4.81 毫莫耳）、DCC(0.992 克，4_81 毫 莫耳）及〇正八（1.680毫升，9.62毫莫耳）。以微波使反應混 合物在150°C下加熱20分鐘。過濾反應混，合物以移除反應 中形成之尿素’且真空移除溶劑。使粗製物質經Fcc(50% 乙酸乙醋/庚烷）純化，獲得灰白色固體之‘（3·(3_氯_4_異 丙氧基苯基）-1，2,4·-号二唑-5-基）苯胺（729毫克，2.211毫莫 耳，產率 50.6%) : LCMS(表 A，方法 b) 3.00 min，（Μ+Η)+ 330·13 〇 製備例編號22 : 3-(4-(3-(3-氣-4-異丙氧基苯基）·ι，2,4-噚二 峻-5-基）苯基胺基）環丁烷曱酸Mix (Z)_3-chloro-N, hydroxy-4-isopropoxyphenyl hydrazine (1 g, 4.37 mmol), aminobenzoic acid (0,660 g, 4.81 mmol) in a microwave vial, ΗΟΒΤ (0·737 g, 4.81 mmol), DCC (0.992 g, 4_81 mmol) and 〇正八 (1.680 ml, 9.62 mmol). The reaction mixture was heated at 150 ° C for 20 minutes with microwave. The reaction mixture was filtered to remove the urea formed in the reaction and the solvent was removed in vacuo. The crude material was purified by Fcc (50% ethyl acetate /Heptane) to afford &lt;(3·(3_chloro_4_isopropoxyphenyl)-1,2,4·-diazole -5-yl) aniline (729 mg, 2.211 mmol, yield 50.6%): LCMS (Table A, Method b) 3.00 min, (Μ+Η)+ 330·13 〇Preparation No. 22 : 3-( 4-(3-(3-Ga-4-isopropoxyphenyl)·ι,2,4-indenyl-5-yl)phenylamino)cyclobutane decanoic acid

ΝΗΝΗ

ΟΗ 127788.doc -188- 200840567 在室溫下於含4-(3-(3-氯-4-異丙氧基苯基卜^，‘噚二唑_ 5-基）苯胺（250毫克，0.531毫莫耳）之甲醇（1478微升）中添 加3-側氧基環丁烷甲酸（60.5毫克，〇531毫莫耳），接著添 加乙酸（814微升’ 14.22毫莫耳）。使反應混合物在室溫下 攪拌5分鐘，接著添加氰基硼氫化鈉（16 67毫克，毫 莫耳）。使反應混合物在室溫吓攪拌隔夜。移除溶劑且使 粗製物質經FCC(5〇%乙酸乙醋/庚烧）純化，獲得白色固體 之3-(4-(3-(3-氣-4-異丙氧基苯基号二唾-5_基）苯基 胺基）環丁烧曱酸（139毫克，〇.3〇2毫莫耳，產率56 9%)。 LCMS(俵 A，方法b) 2,89 min，（M+H)+ 428 2〇。 實例編號S7 U4-(3-(3_氣·4_異丙氧基苯基吟二 峻基）苯基)丙烷胺製備127 127788.doc -188- 200840567 4-(3-(3-chloro-4-isopropoxyphenyl), 'oxadiazole-5-ylphenylaniline aniline (250 mg, 0.531) at room temperature To the methanol (1478 μl) of methanol, 3-oxocyclobutanecarboxylic acid (60.5 mg, 〇 531 mmol) was added followed by acetic acid (814 μl ' 14.22 mmol). Stir at room temperature for 5 minutes, then add sodium cyanoborohydride (16 67 mg, MeOH). The mixture was stirred and stirred at room temperature overnight. The solvent was removed and the crude material was taken to FCC (5 % EtOAc. Purification of vinegar / heptane to give 3-(4-(3-(3- gas-4-isopropoxyphenyl)-dipy-5-yl)phenylamino)cyclobutanthic acid as a white solid (139 mg, 〇.3〇2 mmol, yield 56 9%) LCMS (俵A, method b) 2,89 min, (M+H)+ 428 2 〇. Example No. S7 U4-(3) -(3_Gas·4_Isopropoxyphenylphosphonium) phenyl)propanamine

又 X 在氮氣下將無水氯化鈽（m)(5 57克，22 6g毫莫 益 水四氫。夫⑽0毫升）添加於乾燥之2，圓底瓶中、。使料 懸洋液經超音波數分鐘且接著於室溫1㈣分鐘 使混合物冷卻至-5〇〇c，H經p、灸丄 有 L且緩忮添加曱基鋰（14.13毫， 22.60¾ 莫耳）。60分鐘後，升。^ ^ ^ ^ ^ 。(：，且滴加含4例3_氣4里丙4^使反應冷卻至-50 (虱4·異丙虱基笨基）-1,2,4-啰二唾5 基）苄腈（2.4克，7·〇6毫簟耳、s田立— ~ 毛莫耳）（以通用程序x製備 水THF，以使溫度維持在。 毛升無 隹得在-5〇C以下。使反應維持在_ 以下歷時1小柑，接著使之升 王至恤隔促。次日，使反 127788.doc 200840567Further, anhydrous ruthenium chloride (m) (5 57 g, 22 6 g of miloxime tetrahydrofuran (10) 0 ml) was added to a dry 2, round bottom flask under nitrogen. The suspension was suspended for several minutes by ultrasonic wave and then the mixture was cooled to -5 〇〇c at room temperature for 1 (four) minutes. H was added with p, moxibustion with L and buffered with lithium (14.13 mM, 22.603⁄4 摩尔) ). After 60 minutes, rise. ^ ^ ^ ^ ^. (:, and adding 4 cases of 3_gas 4 liters of 4^ to cool the reaction to -50 (虱4·isopropylidene)-1,2,4-indenylpyrrol-5-ylbenzonitrile ( 2.4 g, 7·〇6 簟 ears, s Tianli - ~ Mao Moer) (Prepare the water THF by the general procedure x to maintain the temperature. The hair liters are not below -5 〇 C. The reaction is maintained at _ The following semester 1 small mandarin, and then make it rise to the king to the shirt. The next day, make the anti-127788.doc 200840567

應冷卻至-50°C，且添加21毫升35% NH4OH終止反應。使 經終止之反應升溫至室溫歷時兩小時。使混合物經矽藻土 過濾且以DCM (4x60毫升）洗滌。收集濾液且在以水洗滌， 並以MgS〇4脫水。減壓移除溶劑且使粗製物質經 HPLC(A=50 mM 乙酸銨；乙腈；30%-70% B歷時 30.0分 鐘（流速21.0¾:升/分鐘）；21.2x250 mm Thermo Hyperprep C18管柱，8 μπι粒子）純化，獲得2-(4-(3-(3-氣-4-異丙氧基 苯基）-1，2,4-崎二唑-5-基）苯基）丙烷-2-胺之乙酸鹽（3 09毫 克 ’ 10.1%)。LCMS(表 1，方法a) Rt=2.61 min; 4 NMR (400 MHz, DMSO-d6) δ ppm 8.14-7.94 (m5 4H), 7.80 (d5 /=8·43 Hz，2H)，7.37 (d，1=8.81 Hz，1H)，4.80 (七重峰， J = 6.04 Hz, 1H)? 1.85 (s, 3H)? 1.39 (s5 6H)5 1.36-1.31 (d? J=6.04 Hz，6H)。 製備例編號23 : 3-(2·(4-(3-(3-氣-4-異丙氧基苯基）-l，2,4-崎二嗤-5-基）苯基）丙-2_基胺基）丙酸甲酯It should be cooled to -50 ° C and the reaction was stopped by the addition of 21 ml of 35% NH 4 OH. The terminated reaction was allowed to warm to room temperature for two hours. The mixture was filtered through celite and washed with DCM (EtOAc). The filtrate was collected and washed with water and dehydrated with MgS〇4. The solvent was removed under reduced pressure and the crude material was purified by HPLC (A=50 mM ammonium acetate; acetonitrile; 30%-70% B for 30.0 minutes (flow rate: 21.03⁄4: liters/min); 21.2 x 250 mm Thermo Hyperprep C18 column, 8 Purification of μπι particles to obtain 2-(4-(3-(3-)-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propane-2- Amine acetate (3 09 mg ' 10.1%). </ RTI> <RTIgt; 1 = 8.81 Hz, 1H), 4.80 (seven peaks, J = 6.04 Hz, 1H)? 1.85 (s, 3H)? 1.39 (s5 6H)5 1.36-1.31 (d? J=6.04 Hz, 6H). Preparation No. 23: 3-(2·(4-(3-(3-Ga-4-isopropoxyphenyl)-l,2,4-oxadiin-5-yl)phenyl)propene- 2_ylamino)methyl propionate

將2-(4-(3-(3-氣-4-異丙氧基苯基）_1，2,4^号二唑-5-基）苯 基）丙烷-2-胺乙酸（132毫克，0.306毫莫耳）添加於裝置有攪 拌棒之5宅升藥瓶中。添加丙稀酸曱酉旨（52.6毫克，0,611毫 莫耳）及MeOH(3.0毫升），將藥瓶蓋住，且以微波輻射 (Biotage Optimizer，300 W)將反應加熱至 120°C 歷時 90 分 鐘。90分鐘後，添加另一份丙烯酸甲酯（52 6毫克，〇 611 127788.doc -190- 200840567 毫莫耳）且使反應在120°C下再進行60分鐘。 使反應冷卻且減壓移除溶劑。使粗製物質經RP—HPLC (A=50mM乙酸銨；B=乙腈；30%-70%B歷時30.0分鐘（流速 21.0¾ 升/分鐘）；21.2x250mm Thermo Hyperprep C18管柱， 8 μπι粒子）純化，獲得3_(2-(4-(3-(3-氣-‘異丙氧基苯基）-1，2,4-崎二唾-5-基）苯基）丙-2-基胺基）丙酸甲酯（83.5毫克， 59.7%)。LCMS(表 1，方法 F) Rt=2.78 min，m/z=458.29 (M=H)、 實例編號58 : 3-(2-(4-(3_(3_氣-4_異丙氧基苯基）-i，2,4-噚 二唑-5_基）苯基）丙-2-基胺基）丙酸之製備2-(4-(3-(3-Ga-4-isopropoxyphenyl)_1,2,4^diazol-5-yl)phenyl)propan-2-amineacetic acid (132 mg, 0.306 millimoles) was added to the 5 home liter bottle with a stir bar. Add acrylic acid (52.6 mg, 0,611 mmol) and MeOH (3.0 mL), cover the vial and heat the reaction to 120 °C for 90 minutes with microwave irradiation (Biotage Optimizer, 300 W) . After 90 minutes, another portion of methyl acrylate (52 6 mg, 611 611 127788.doc - 190 - 200840567 mM) was added and the reaction was allowed to proceed for an additional 60 minutes at 120 °C. The reaction was allowed to cool and the solvent was removed under reduced pressure. The crude material was purified by RP-HPLC (A = 50 mM ammonium acetate; B = acetonitrile; 30% - 70% B for 30.0 minutes (flow rate 21.03⁄4 liter / min); 21.2 x 250 mm Thermo Hyperprep C18 column, 8 μπι particles). Obtaining 3_(2-(4-(3-(3- gas-'isopropoxyphenyl)-1,2,4-succinyl-sial-5-yl)phenyl)propan-2-yl) Methyl propionate (83.5 mg, 59.7%). LCMS (Table 1, Method F) Rt = 2.78 min, m/z = 458.29 (M = H), </RTI> Example 58: 3-(2-(4-(3_(3_-)) Preparation of -i,2,4-oxadiazol-5-yl)phenyl)propan-2-ylamino)propionic acid

使3-(2-(4-(3-(3-氯-4-異丙氧基苯基）-1，2,4·呤二唑-5-基) 苯基）丙-2-基胺基）丙酸甲酯（83毫克，0.181毫莫耳）溶於乙 醇（4毫升）中且添加NaOH(4毫升，8.00毫莫耳）。使混合物 在室溫下及氮氣中攪拌，20分鐘後，滴加乙酸中和反應。 水性混合物經冷凍並凍乾。將凍乾後獲得之固體置於DCM 中’經過濾且以DCM洗滌。濃縮濾液且置於乙醚中，獲得 稍渾濁之溶液。滴加1 N HC1直到形成白色沉澱物為止。 過濾收集物質，以乙醚洗滌且於真空烘箱中乾燥，獲得3_ (2-(4-(3-(3-氣-4-異丙氧基苯基）-1，2,4-噚二唑-5-基）苯基） 丙-2-基胺基）丙酸之鹽酸鹽（61·5毫克，70.6%)。LCMS (表 1 ’ 方法 F) Rt=1.98 min，m/z=444.29 (M=H)+; 4 NMR(400 127788.doc -191 - 2008405673-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4·oxadiazol-5-yl)phenyl)propan-2-ylamine Methyl propionate (83 mg, 0.181 mmol) was dissolved in ethanol (4 mL) and NaOH (4 mL, EtOAc. The mixture was stirred at room temperature under nitrogen, and after 20 minutes, acetic acid was neutralized by dropwise addition. The aqueous mixture was frozen and lyophilized. The solid obtained after lyophilization was placed in DCM 'filtered and washed with DCM. The filtrate was concentrated and placed in diethyl ether to give a slightly cloudy solution. 1 N HCl was added dropwise until a white precipitate formed. The material was collected by filtration, washed with diethyl ether and dried in a vacuum oven to give 3-(2-(3-(3-(4-(4-(4-((((((())))) 5-Hydroxy)phenyl)propan-2-ylamino)propionic acid hydrochloride (61.5 mg, 70.6%). LCMS (Table 1 'Method F) Rt = 1.98 min, m/z = 444.29 (M = H) +; 4 NMR (400 127788.doc -191 - 200840567

MHz，DMSO-d6) δ ppm 8.32 (d，J=8.57 Hz，2H)，8.12 (d， J=2.08 Hz, 1H)，8·03 (dd，J=8.64，2.10 Hz，1H)，7.85 (d， J=8.59 Hz，2H)，7.25 (d，J=8.78 Hz，1H)，4·79 (七重峰， J=6.11 Hz，1H)，2·95 (t，J=6.20 Hz，2H)，2.44 (t，J = 6.17 Hz， 2H)，1.84 (s，6H)，1·40 (d，J=6.04 Hz，6H)。 127788.doc 192-MHz, DMSO-d6) δ ppm 8.32 (d, J=8.57 Hz, 2H), 8.12 (d, J=2.08 Hz, 1H), 8·03 (dd, J=8.64, 2.10 Hz, 1H), 7.85 ( d, J=8.59 Hz, 2H), 7.25 (d, J=8.78 Hz, 1H), 4·79 (seven peaks, J=6.11 Hz, 1H), 2·95 (t, J=6.20 Hz, 2H) , 2.44 (t, J = 6.17 Hz, 2H), 1.84 (s, 6H), 1·40 (d, J = 6.04 Hz, 6H). 127788.doc 192-

Claims (1)

200840567 十、申請專利範圍： 1 · 一種下式I之化合物，200840567 X. Patent application scope: 1 · A compound of the following formula I, 式I 其醫藥可接受性鹽、生物上活性代謝物、溶劑化物、水 合物、前藥、對映異構物或立體異構物，其中 L為一鍵或視情況取代之（c广C3)烷基；A pharmaceutically acceptable salt, biologically active metabolite, solvate, hydrate, prodrug, enantiomer or stereoisomer thereof, wherein L is a bond or optionally substituted (c-C3) alkyl; R1為-C(0)-NH-苯基、·贿⑼十南基鲁_广視 情況取代之苯基、_〇·視情況取代之（c】_c3)烧基、_s_規 情況取代之（Cl-c3)院基、視情況取代之（C2_C6)院基、視 情況取代…、視情況取代之(CVC6)環貌基、 -仰2胸烧基、四氫苯并咬喃基、Μ基m南 基、視情況取代之二氫異㈣基、視情況取代之味 嗤基 '視情況取代之㈣基、視情況取代之異十坐基、 視情況取代之嗎琳基、視情況取代之萘基、視情況取代 之苯基、-0-CH2-苯基、苯基、_〇_視情況取代之苯 基、視情況取代之錢基、視情況取代之㈣基、視情 況取代…基、視情況取代之喷d定基、視情況取代之 料咬基、視情況取代之W四氫異㈣基、視情況 取代之㈣基、視情況取代之5，Μ，8·四氫㈣并n，2_a] °比嗓基、視情況取代之料基、视情況取代之㈣基、 127788.doc 200840567 視N况取代之噻唑基或視情況取代之噻吩基； R 為 ΒΓ、cn、cf3、cn 或-ckcvco 燒基； R3為視情況取代之犯_c8)烧基、（c4-c5)稀基、（(V Cs)炔基、視情況取代之-(C^C6)環烷基、_(C2_C3)烷基-0-視情況取代之（Cl_C3)烷基、_(Ci_C3)烷基_咪唑基、 -(Ci-C3)烷基-嗎啉基、_(Ci_C3)烷基_視情況取代之笨 基e(Cl-C3)烷基·視情況取代之哌嗪基、_(Ci_C3)烷基_ 吼嘻咬基、.(Ci_C3m基m、_(Ci_c狀基·嗟吩 基、四氫呋喃基或噻唑基；且 R6 為 Η ; 但限制條件為 R1不為視情況取代之環己基、-C(〇)_環己基或鲁環 己基取代； &amp; 當L為（C^C：3)烷基時，Ri不為視情況取代之昱噚唑 基； ’、R1 is -C(0)-NH-phenyl, bribe (9) Ten Nanjilu _ replaced by phenyl, _ 〇 视 视 视 视 视 视 视 视 视 视 视 取代 取代 取代 取代 取代 取代 取代 取代 取代 取代 取代(Cl-c3) hospital base, replace the (C2_C6) yard base as appropriate, replace it as appropriate, replace CVC6 ring base, - 2 chest burn base, tetrahydrobenzoate base, Μ Substituted m-Nanji, optionally substituted dihydroiso(tetra)yl, optionally substituted as a base, 'substituting the (iv) base as appropriate, replacing the different bases as appropriate, replacing the Lin Keji as appropriate, as appropriate Naphthyl, optionally substituted phenyl, -0-CH2-phenyl, phenyl, _ 〇 _ phenyl substituted as appropriate, optionally replaced by the base, optionally substituted (four), replace as appropriate... Base, depending on the situation, replace the base, replace the bite base as appropriate, replace the W tetrahydroiso(tetra) group as appropriate, replace the (iv) base as appropriate, replace 5, Μ, 8 · tetrahydro (4) as appropriate n,2_a] ° than sulfhydryl, optionally substituted base, optionally substituted (iv), 127788.doc 200840567 thiozolyl substituted according to N condition or optionally substituted thienyl; R is Β , cn, cf3, cn or -ckcvco alkyl; R3 is replaced by _c8) alkyl, (c4-c5) dilute, ((V Cs) alkynyl, as appropriate - (C^C6 Cycloalkyl, _(C2_C3)alkyl-0- optionally substituted as (Cl_C3)alkyl, _(Ci_C3)alkyl-imidazolyl, -(Ci-C3)alkyl-morpholinyl, _(Ci_C3 Alkyl _ optionally substituted stupid e (Cl-C3) alkyl group - as appropriate, piperazinyl, _(Ci_C3)alkyl _ 吼嘻 基, . (Ci_C3m group m, _ (Ci_c-based嗟 基, tetrahydrofuranyl or thiazolyl; and R 6 is Η; but the limitation is that R 1 is not optionally substituted cyclohexyl, -C(〇)_cyclohexyl or rucyclohexyl; &amp; when L is ( When C^C: 3) alkyl group, Ri is not an oxazolyl group optionally substituted; ', 當R3為視情況取代之（Cl)烷基時，L_Rl不為環己基或 -CH2-環己基；且 限制條件為該化合物不為下列化合物When R3 is optionally substituted (Cl)alkyl, L_R1 is not cyclohexyl or -CH2-cyclohexyl; and the limitation is that the compound is not the following compound 2.如請求項1之化合物’其丨係視情況經—或多個獨立 選自下列之取代基取代：Br、C卜F、CF3、CN、側氧 基視h況取代之（C1-C6)烷基、視情況取代之（C2_C6)烯 基、視情況取代之胺基、視情況取代之（C3_C6)環烷 127788.doc -2- 200840567 基、-ch2-視情況取代之哌啶基、-C(〇)-視情況取代之 (CpCJ烷基、-CCCO-NR-CCrCd烷基、-c(o)-o-視情況取 代之（CVC6)烷基、-CM見情況取代之（CVC6)烷基、-NH-(C3_C6)環烷基、-NH-C(0)-0-(Ci-C3)烷基、-s(o)2-N(R9)2、-S(0)2-NH-視情況取代之（(VC4)烷基、-NH-視 情況取代之（CVC6)烷基、-NH-C(O)-呋喃基、-NH-S(0)2-視情況取代之苯基、視情況取代之吡啶基、2. The compound of claim 1 wherein the oxime is substituted by a substituent or independently selected from the group consisting of Br, C, F, CF3, CN, and pendant oxy groups (C1-C6) Alkyl, optionally substituted (C2_C6)alkenyl, optionally substituted amino, optionally substituted (C3_C6)cycloalkane 127788.doc -2- 200840567, -ch2-optionally substituted piperidinyl, -C(〇)-substituted as appropriate (CpCJ alkyl, -CCCO-NR-CCrCd alkyl, -c(o)-o- optionally substituted (CVC6) alkyl, -CM as appropriate (CVC6 Alkyl, -NH-(C3_C6)cycloalkyl, -NH-C(0)-0-(Ci-C3)alkyl, -s(o)2-N(R9)2, -S(0) 2-NH-substituted as appropriate ((VC4) alkyl, -NH- optionally substituted (CVC6) alkyl, -NH-C(O)-furanyl, -NH-S(0)2- depending on the case Substituted phenyl, optionally substituted pyridyl, 其中R為Η或（CVC3)烷基；且 其中各R9係獨立選自Η或視情況取代之（Cl-C6)烷基。 3·如請求項2之化合物，其中該化合物為式^之化合物：Wherein R is hydrazine or (CVC3)alkyl; and wherein each R9 is independently selected from hydrazine or optionally substituted (Cl-C6)alkyl. 3. The compound of claim 2, wherein the compound is a compound of formula: 式la 其中L為一鍵。 ㈢求項3之化合物’其中R為視情况取代之苯基或視 f月况取代之叫| π朵基。 127788.doc 200840567Where la is a bond. (3) The compound of claim 3 wherein R is a phenyl group substituted as appropriate or replaced by a π-based group. 127788.doc 200840567 5·如請求項4之化合物，其中該化合物 為：5. The compound of claim 4, wherein the compound is: 其中y為1或2。 6·如請求項1之化合物，其中 匕為視情況取代之（CrC;)烷基； 2烟.苯基、·職⑼十m_s(〇)2_視 :况取代之苯基、視情況取代之仰錢基、I 氧基'視情況取代之（μ)環烧基、Where y is 1 or 2. 6. The compound of claim 1, wherein hydrazine is optionally substituted (CrC;) alkyl; 2 sm. phenyl, occupant (9) ten m_s (〇) 2 _: phenyl substituted, replaced as appropriate Substituting (μ) cycloalkyl, 現情况取代之咪唑基、嗎啉 ”唧暴視情況取代之萘基、視 ΐ月况取代之苯基、視情 α/, , ^ 取代之本虱基、視情況取代之 又口禾基、視情況取代之哌啶基、 丞说^況取代之吡啶基、 削月況取代之吡咯啶基或視情況取代之噻吩基； R2 為 C1 ; 土’ R3為異丙基；且 R6為 Η 〇Substituted imidazolyl, morpholine, "naphthyl group substituted by violent catastrophe, phenyl substituted by ΐ ΐ 、 、 、 、 、 、 、 、 、 、 、 取代 取代 取代 取代 取代 取代 取代 取代 取代 取代Substituted piperidinyl, pyridyl substituted, pyrrolidinyl substituted or optionally substituted thienyl; R2 is C1; soil 'R3 is isopropyl; and R6 is Η 〇 如％求項6之化合物，其中l為CH2且R1為 笨基或視情況取代之（C3_C6)環烷基。 視情況取代之 127788.doc 200840567 8·如明求項7之化合物，其中Ri係經一或多個獨立選自F、 一甲胺基及苯氧基之取代基取代。 9. 一種式II之化合物，A compound of claim 6, wherein l is CH2 and R1 is a stupid or optionally substituted (C3_C6)cycloalkyl. The compound of claim 7, wherein Ri is substituted with one or more substituents independently selected from the group consisting of F, a methylamino group, and a phenoxy group. 9. A compound of formula II, 式II 瞻其醫藥可接受性鹽、生物上活性代謝物、溶劑化物、水 合物、前藥、對映異構物或立體異構物，其中 Y為一鍵； L為一鍵或ch2 ; R為視情況取代之（C1-C4)烷基、視情況取代之吲哚基 或視情況取代之苯基； R2為 cf3 ; R3為Η、嗎啉基或（c3-c5)環烷基；且 # R6 為 H。 10·如請求項9之化合物，其中Ri為視情況取代之苯基且反3 為嗎啉基。 11·如請求項1〇之化合物，其中Ri係視情況經一或多個獨立 選自下列之取代基取代·· Cl、視情況取代之（Cl_c3)烷 基、 127788.doc 200840567Formula II is a pharmaceutically acceptable salt, a biologically active metabolite, a solvate, a hydrate, a prodrug, an enantiomer or a stereoisomer wherein Y is a bond; L is a bond or ch2; Substituted (C1-C4)alkyl, optionally substituted fluorenyl or optionally substituted phenyl; R2 is cf3; R3 is fluorene, morpholinyl or (c3-c5)cycloalkyl; # R6 is H. 10. The compound of claim 9, wherein Ri is optionally substituted phenyl and trans 3 is morpholinyl. 11. A compound according to claim 1 wherein Ri is optionally substituted by one or more substituents selected from the group consisting of: Cl, optionally substituted (Cl_c3) alkyl, 127788.doc 200840567 12· —種式III之化合物，12·—a compound of formula III, 其醫藥可接受性鹽、生物上活性代謝物、溶劑化物、水 合物、前藥、對映異構物或立體異構物，其中 D為CH或N ; Y為一鍵； L為一鍵； R1為視情況取代之苯基； R2 為 Η ; R3為Η ;且 R6為視情況取代之（Ci_C3)烷基。 13.如明求項12之化合物，其中Rl係經a及異丙氧基取代。 14· 一種式（iv)之化合物，a pharmaceutically acceptable salt, a biologically active metabolite, a solvate, a hydrate, a prodrug, an enantiomer or a stereoisomer, wherein D is CH or N; Y is a bond; L is a bond; R1 is a phenyl group optionally substituted; R2 is Η; R3 is Η; and R6 is optionally substituted (Ci_C3)alkyl. 13. The compound of claim 12, wherein R1 is substituted with a and isopropoxy. 14. A compound of formula (iv), (IV) 或其醫藥可接受性鹽、溶劑化物、水合物、代謝物、前 127788,doc 200840567 藥、對映異構物或立體異構物， 其中： X為N或CR4 ; L為一鍵、-CH2Ch2_、（C3_C6)環烷基或-chr5_; Y為-〇-、-NR7-或-c(R7)(r7_)_ ;(IV) or a pharmaceutically acceptable salt, solvate, hydrate, metabolite thereof, 127788, doc 200840567, enantiomer or stereoisomer, wherein: X is N or CR4; L is a bond , -CH2Ch2_, (C3_C6)cycloalkyl or -chr5_; Y is -〇-, -NR7- or -c(R7)(r7_)_; R為視h況取代之芳基、視情況取代之雜芳基、視情 況取代之雜環基、視情況取代之-(C^Ce)烷基-0-(Cl-C3) 烷基、視情況取代之_(Ci_C6)烷基烷基_〇_(c「 C3)烷基、視情況取代之_(CVC6)烷基_〇_芳基、烷基硫基 烷基、未經取代之（C^C：5)烷基、經取代之（Cl_C6)烷 基、-COR9、視情況取代之_〇_(Ci_C3)烷基、 -N(R )(R )、-N(R7)S02-R9或視情況取代之（c^c6)環烷 基’且其中R1不為經取代之環戊并噻吩 (cyclopeantathiophene)、鹵σ塞吩、經取代之二氫茚 (indan)或經取代之色稀@同（chr〇menone); R2及R6可相同或不同且獨立為Η、-(CVCO烷基、 (C!-C3)烧基、-CF3、CN、i 基或-COO-(C〗-C4)燒基； R3為視情況取代之芳基、視情況取代之雜環基、視情 況取代之雜芳基、視情況取代之（C3-C6)環烧基、 -(CH2)n-R9、-CO-OR9、-CO-R9、-CON(R7)(R9)、 -N(R7)(R9)、-SOR9、-S〇2R9及視情況取代之直鏈或分支 (Ci-C8)烷基鏈，該烷基鏈視情況包含嵌在烷基鏈中之 _CO_、_COO-、-SO-、_S02-、_CONH_、-NHCO- Ή 或-O-基，且當Y為O時’ R3不為烧基二氮雜環庚燒、 127788.doc 200840567 -C(CH3)2C〇〇CH2CH3 或-CH2CH2N(CH2CH3)2，且當 丫為_ CH2-時’ r3不為-CH2COOH ; 或Y為一鍵且R3為視情況取代之嗎啉基； R4為 Η、_(Cl-c4)烷基、-CKCVC3)烷基、_CF3、_CN 或 鹵基； R5為 H、〇-(Cl_c3)烧基或（Cl-C3)烧基； R或R、次出現係獨立為Η或視情況取代之（c〗_c3)院 基； R為11、視情況取代之CH3或-COR9 ; R為氫、視情況取代之（Cl_C3)烷基、視情況取代之炔 基、視情況取代之芳基、視情況取代之雜芳基、視情況 取代之雜環基或視情況取代之（CrC6)環烷基；且 η為 1、2、3 或 4 ; 但限制條件為 R1不為視情況取代之Μ基或_c叫視情況取代之咬 喃基； 3 R不為視情況取代之喹啉基； R9不為視情況取代之環丙基、視情況取代之淨己美 =取:之吱喃基、視情況取代之咪録、視情二取 :…見’以取代之萘基、視情況取代之哌唪 土、視情況取代之Μ基、視情心代之 況取代之喹啉基； ，、基或視十月 R不為經-〇:(〇)-環戊基、視情況 jf 丁且卢π * 又&lt; %戊基、-C(O)- 基·&quot; 丁基、糊·環己基或視情況取代之環己2 127788.doc 200840567 代； R不為經-c(o)-環丙基取代； 當R3為CHs或4-氯苯基甲基時，L Κ不為％丙基、J哀 戊基、視情況取代之環己基、·CH 己基、-NH-環己 基、-CH2CH2_環己基或視情況取代之吡唑美· 當Y為0時，V不為-(c〇_c4)燒基_視情況取土代之異㈣ 基或視情況取代之吡唑基； 當L為㈣烧基時’ Ri不為視情況取代之旦十坐 基； ~ 之環丁基、視情況 _ch2_視情況取代之 視情況取代之吡唑 當L為一鍵時，Ri不為視情況取代 取代之1衣己基、視情況取代之萘基、 萘基、-CHrO-視情況取代之萘基、 基或四氫苯并呋喃基；R is an aryl group substituted, optionally substituted heteroaryl, optionally substituted heterocyclic group, optionally substituted -(C^Ce)alkyl-0-(Cl-C3)alkyl, Substituting _(Ci_C6)alkylalkyl-〇-(c"C3)alkyl, optionally substituted _(CVC6)alkyl-〇-aryl, alkylthioalkyl, unsubstituted ( C^C: 5) alkyl, substituted (Cl_C6) alkyl, -COR9, optionally substituted _〇_(Ci_C3)alkyl, -N(R)(R), -N(R7)S02- R9 or optionally substituted (c^c6)cycloalkyl' and wherein R1 is not a substituted cyclopeantathiophene, a halogen σ-phene, a substituted indan or a substituted color Rare @同(chr〇menone); R2 and R6 may be the same or different and independently Η, -(CVCO alkyl, (C!-C3) alkyl, -CF3, CN, i or -COO-(C) -C4) an alkyl group; R3 is an optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted heteroaryl group, optionally substituted (C3-C6) cycloalkyl, -(CH2)n- R9, -CO-OR9, -CO-R9, -CON(R7)(R9), -N(R7)(R9), -SOR9, -S〇2R9 and optionally substituted straight or branched (Ci-C8 Alkyl chain The chain optionally includes _CO_, _COO-, -SO-, _S02-, _CONH_, -NHCO- Ή or -O- groups embedded in the alkyl chain, and when Y is O, 'R3 is not azodiazepine Heterocyclic heptane, 127788.doc 200840567 -C(CH3)2C〇〇CH2CH3 or -CH2CH2N(CH2CH3)2, and when 丫 is _CH2-, 'r3 is not -CH2COOH; or Y is a bond and R3 is Substituted morpholinyl; R4 is hydrazine, _(Cl-c4)alkyl, -CKCVC3)alkyl, _CF3, _CN or halo; R5 is H, 〇-(Cl_c3) alkyl or (Cl-C3) Burning base; R or R, secondary occurrence is independent or replaced by (c)_c3); R is 11, replace CH3 or -COR9 as appropriate; R is hydrogen, optionally substituted (Cl_C3) Alkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted (CrC6)cycloalkyl; and η is 1, 2 , 3 or 4; but the restriction condition is that R1 is not substituted by the sulfhydryl group or _c is replaced by a thiol group as the case may be; 3 R is not a quinolinyl group which is optionally substituted; R9 is not a ring which is optionally substituted Propyl, as the case replaces the net beauty = : 吱 吱 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 取代 取代 取代 取代 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱 吱Quinolinyl; ,, or the valence of October is not 经-〇:(〇)-cyclopentyl, depending on the case, jf butyl and π * and &lt; % pentyl, -C(O)-yl·&quot Butyl, paste, cyclohexyl or optionally substituted cyclohexane 2 127788.doc 200840567 generation; R is not substituted by -c(o)-cyclopropyl; when R3 is CHs or 4-chlorophenylmethyl , L Κ is not % propyl, J pentyl, optionally substituted cyclohexyl, · CH hexyl, -NH-cyclohexyl, -CH 2 CH 2 _ cyclohexyl or optionally substituted pyrazol · when Y is 0 , V is not - (c〇_c4) burning base _ depending on the case, the soil is replaced by (4) base or substituted pyrazol group; when L is (four) burning base 'R is not replaced by the situation Base; ~ cyclobutyl, depending on the case _ch2_, as appropriate, substituted pyrazole, when L is a bond, Ri is not substituted for the substituted hexyl group, optionally substituted naphthyl, naphthalene Base, -CHrO- optionally substituted naphthyl Group or a tetrahydro- benzofuranyl; 該化合物不為The compound is not 其中R3為視情況取代之派„秦基或視情況 該化合物不為 i wvO^i O-N 127788.doc -9* 200840567 其中R1為視情況取代之吼啶基或3 -氯苯基且-Υ-R3為 -NH-C(O)-視情況取代之苯基； -0-視情況取代之吡啶基； -NH-C(0)-0CH3 ; -CH2·視情況取代之略唤基， -0-視情況取代之（CpCO烷基； -CH2-嗎啉基；或 -o-c(o)-視情況取代之吡啶基； 但限制條件為該化合物不為Wherein R3 is substituted as appropriate. Qinji or, as the case may be, the compound is not i wvO^i ON 127788.doc -9* 200840567 wherein R1 is optionally substituted acridinyl or 3-chlorophenyl and -Υ- R3 is -NH-C(O)-optionally substituted phenyl; -0-optionally substituted pyridyl; -NH-C(0)-0CH3; -CH2.substituted as a base, -0 - substituted as appropriate (CpCO alkyl; -CH2-morpholinyl; or -oc(o)- optionally substituted pyridyl; but with the proviso that the compound is not 其中 L為 CH2、CH(CH3)或 CH2CH2 ; Y為Ο或CH2 ; R2 為 Η 或 OCH3 ; R3 為 CH3 或 OCF3 ;且 R為H或N02 ; 但限制條件為該化合物不為Wherein L is CH2, CH(CH3) or CH2CH2; Y is Ο or CH2; R2 is Η or OCH3; R3 is CH3 or OCF3; and R is H or N02; but the limitation is that the compound is not 限制條件為該化合物不為The restriction is that the compound is not 127788.doc •10- 200840567 其中R1為苯基、4-氯苯基、哌啶基或噻吩基。 15.如請求項14之化合物，其中各取代基或視情況選用之取 代基獨立為一或多個Ri〇基，其中R】o為視情況取代之烷 基、烯基、視情況取代之烷氧基、烷氧基烷氧基、烷氧 基烷基、烷氧基羰基、烷氧基羰基雜環烷氧基、烷基、 烷基胺基、烷基羰基、烷基酯、烷基-〇-C(〇)_、烷基_雜 環基、烷基-環烷基、烷基-腈、烷基磺醯基、炔基、醯 胺基、胺基、胺基烷基、胺基烷氧基、胺基羰基、甲 f 腈、羰基烷氧基、曱醯胺基、CF3、CN、、 -C(0)H、_C(0)-C(CH3)3、-OH、_C(0)〇-烧基、_c(0)0· 環烧基、-c(0)0-雜環基、-C(o)·烷基、-C(O)-環烷基、 -c(0&gt;雜環基、CN、環烷基、二烷基胺基、二烷基胺基 烧氧基、二烷基胺基羰基烷氧基、二烷基胺基羰基、二 烧基胺基磺醯基、-C(〇)_〇Ra、鹵素、雜環基、雜環基烷 基、雜環基氧基、羥基、羥基烷基、硝基、側氧基、苯 基、_S02CH3、-S02CF3、績醢基、四唾基、α塞吩基烧氧 ^ 基、三氟甲基羰基胺基、三氟甲基磺醯胺基、雜環基烷 氧基、雜環基-S(0)p、環烷基-S(0)p、烷基-S-、雜環基-s、雜環烷基、環烷基烷基、雜環基硫基、環烷基硫 基、N-烷基胺基及N，N-二烷基胺基，其中Ra為烷基、雜 環燒基或雜環基，且p為1或2。 16·如請求項14之化合物，其具有式（lva): 127788.doc 200840567127788.doc •10- 200840567 wherein R1 is phenyl, 4-chlorophenyl, piperidinyl or thienyl. 15. The compound of claim 14 wherein each substituent or, optionally, a substituent is independently one or more Ri indenyl, wherein R]o is optionally substituted alkyl, alkenyl, optionally substituted alkane Oxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy, alkyl, alkylamino, alkylcarbonyl, alkyl ester, alkyl- 〇-C(〇)_, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkylsulfonyl, alkynyl, decylamino, amine, aminoalkyl, amine Alkoxy, aminocarbonyl, mefonitrile, carbonyl alkoxy, decylamino, CF3, CN, -C(0)H, _C(0)-C(CH3)3, -OH, _C( 0) 〇-alkyl, _c(0)0·cycloalkyl, -c(0)0-heterocyclyl, -C(o)·alkyl, -C(O)-cycloalkyl, -c( 0&gt; Heterocyclyl, CN, cycloalkyl, dialkylamino, dialkylamino alkoxy, dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, dialkylaminosulfonate Indenyl, -C(〇)_〇Ra, halogen, heterocyclic group, heterocyclylalkyl, heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, pendant oxy, phenyl, _S02CH3, -S02CF3, fluorenyl, tetras-sulphate, α-phenantyloxycarbonyl, trifluoromethylcarbonylamino, trifluoromethylsulfonylamino, heterocyclylalkoxy, heterocyclyl-S ( 0) p, cycloalkyl-S(0)p, alkyl-S-, heterocyclyl-s, heterocycloalkyl, cycloalkylalkyl, heterocyclylthio, cycloalkylthio, N An alkylamino group and an N,N-dialkylamino group, wherein Ra is an alkyl group, a heterocycloalkyl group or a heterocyclic group, and p is 1 or 2. 16. The compound of claim 14 which has the formula (lva): 127788.doc 200840567 水合物或立體異構 或其生理上可接受性鹽、溶劑化物 物，其中： L為一鍵、-CH2CH2-或（C3-C6)環烷基； Rl為視情況取代之芳基、視情況取代之雜芳基或視情 況取代之-CHCrCO烷基； R2為鹵素或CF3 ;且 R3為直鏈或分支之視情況取代之（CrC8)烷基或視情況 取代之（C3-C6)環烷基。 17·如请求項16之化合物，其中r2為ci或cf3。 18·如凊求項17之化合物，其中R2為ci。 19·如凊求項14之化合物，其具有式（Ivb) ··a hydrate or a stereoisomer or a physiologically acceptable salt or solvate thereof, wherein: L is a bond, -CH2CH2- or (C3-C6)cycloalkyl; R1 is an optionally substituted aryl group, as the case may be. Substituted heteroaryl or optionally substituted -CHCrCOalkyl; R2 is halo or CF3; and R3 is a straight or branched, optionally substituted (CrC8) alkyl or optionally substituted (C3-C6) naphthenic base. 17. The compound of claim 16, wherein r2 is ci or cf3. 18. The compound of claim 17, wherein R2 is ci. 19. The compound of claim 14, which has the formula (Ivb) · (IVb) 或其生理上可接受性鹽、 映異構物或立體異構物， 溶劑化物、水合物、前藥、對 其中： L為一鍵、-CH2CH2-或（C3-C6)環烷基； R為甲苯基、吼咬基、異p号唑基、σ比唤基、甲基吼噃 基、乙酮基苯基、苯基、胺基曱酸第三丁酯、苄腈、二 乙胺基笨基、噻吩基、Ν_甲基吼咯基、鹵基吨啶基或甲 基吡啶基；且 127788.doc -12- 200840567 R3為異丁基、環丙基甲基、3-甲氧基丙基、1-乙基丙 基、第二丁基、異丙基、第三丁基或三氟乙基。 20·如請求項14之化合物，其具有式（IVc):(IVb) or a physiologically acceptable salt, exemplified or stereoisomer thereof, solvate, hydrate, prodrug, wherein: L is a bond, -CH2CH2- or (C3-C6) naphthenic R is a tolyl group, a tick base, an iso-p-zolyl group, a σ-callyl group, a methyl fluorenyl group, an ethyl ketone phenyl group, a phenyl group, an amino decanoic acid tert-butyl ester, a benzonitrile, a second Ethylamino, thienyl, fluorenyl-methyl fluorenyl, halotolyl or methylpyridyl; and 127788.doc -12- 200840567 R3 is isobutyl, cyclopropylmethyl, 3- Methoxypropyl, 1-ethylpropyl, t-butyl, isopropyl, tert-butyl or trifluoroethyl. 20. The compound of claim 14 which has the formula (IVc): 或其生理上可接受性鹽、溶劑化物、水合物或立體異構 物，其中： L為一鍵或-CH2CH2-; R1為甲苯基、吼啶基、曱基吼嗪基、苯基、胺基甲酸 第三丁酯、苄腈、噻吩基、N_甲基咄咯基或鹵基吡啶 基；且 R3為異丁基、異丙基、環丙基甲基、3_甲氧基丙基、 1-乙基丙基、第二丁基或異丙基。 21.如請求項20之化合物，其中R3為異丙基。Or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: L is a bond or -CH2CH2-; R1 is tolyl, acridine, decylpyridazinyl, phenyl, amine Tert-butyl carboxylic acid, benzonitrile, thienyl, N-methylfluorenyl or halopyridinyl; and R3 is isobutyl, isopropyl, cyclopropylmethyl, 3-methoxypropyl , 1-ethylpropyl, second butyl or isopropyl. 21. The compound of claim 20, wherein R3 is isopropyl. 22·如請求項21之化合物，其中Ri為甲笨基或鹵基吼啶基。 23.如請求項22之化合物，其中R1為氣吼啶基或氟吼啶基。 24· —種醫藥組合物，其包括如請求項1、9、丨2或14之化人 物或其醫藥可接受性鹽、溶劑化物、水合物、代謝物、 前藥或立體異構物及醫藥可接受性稀釋劑或载劑。 25. —種如請求項1、9、12或14之化合物或其醫藥可接受性 鹽、溶劑化物、水合物、代謝物、前藥或立體異構物之 用迷’係用以製造供治療免疫疾病之藥品。 26·如請求項25之用途，其中該免疫疾病為自體免疫疾病。 127788.doc -13- 200840567 27,如請求項26之用途，其中該自體免疫疾病為風濕性關節 炎、活動型慢性肝炎、阿迪森症（Addis〇n，s以化⑽匀、 抗-磷脂質症候群、特應性過敏、自體免疫萎縮性胃炎、 胃酸缺乏症（achlorhydra)自體免疫、腹腔性疾病（CeHac Disease)、克隆氏症（Cr〇hn’s Disease)、克新氏症候群 (Cushing’s Syndrome)、皮肌炎、古德帕斯策症候群 (Goodpasture’s Syndrome)、格維氏症（Grave，s Disease)、22. The compound of claim 21, wherein Ri is a phenyl group or a halopyridinyl group. 23. The compound of claim 22, wherein R1 is a gasridinyl or fluoroacridinyl group. 24. A pharmaceutical composition comprising a subject, as claimed in claim 1, 9, or 2 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof, and a pharmaceutical Acceptable diluent or carrier. 25. Use of a compound of claim 1, 9, 12 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof for manufacture Medicine for immune diseases. 26. The use of claim 25, wherein the immune disease is an autoimmune disease. 127788.doc -13- 200840567 27, wherein the use of claim 26, wherein the autoimmune disease is rheumatoid arthritis, active chronic hepatitis, Addison, (Addis〇n, s (10), anti-phospholipid Symptoms, atopic allergy, autoimmune atrophic gastritis, achlorhydra autoimmune, celiac disease, Cr〇hn's Disease, Cushing's Syndrome ), dermatomyositis, Goodpasture's Syndrome, Grave, s Disease, 橋本氏甲狀腺炎（Hashimoto’s thyroiditis)、特發性腎上 腺萎縮、特發性血小板減少症、蘭伯特-依頓症候群 (Lambert-Eaton Syndrome)、狼瘡樣肝炎、混合性結締組 織疾病、天皰瘡、尋常型天皰瘡、惡性貧血、水晶體原 性葡萄膜炎（phacogenic uveitis)、結節性多動脈炎、原 發性膽汁性肝硬化、原發性硬化性膽道炎、牛皮癖、雷 諾氏症候群（Raynauds Syndrome)、雷特氏症候群 (Reiter’s Syndrome)、復發性多軟骨炎、斯密特氏症候群 (Schmidt’s Syndrome)、修格蘭氏症候群（sjogren，s Syndrome)、交感性眼炎、高安氏動脈炎（Takayasu，s Arteritis)、顳動脈炎、甲狀腺毒症（thyrotoxicosis)、狼 瘡、風濕症關節炎、B型胰島素抗性、潰瘍性結腸炎或 知格納氏肉芽腫（Wegener’s granulomatosis)。 28· —種如請求項！、9、12或14之化合物或其醫藥可接受性 鹽、溶劑化物、水合物、代謝物、前藥或立體異構物之 用途，其係用以製造供治療中樞神經系統疾病之藥品。 29· —種如請求項1、9、12或14之化合物或其醫藥可接受性 127788.doc -14 - 200840567 鹽、溶劑化物、水合物、代謝物、前藥或立體異構物之 用途，其係用以製造供治療多發性硬化之藥品。Hashimoto's thyroiditis, idiopathic adrenal atrophy, idiopathic thrombocytopenia, Lambert-Eaton Syndrome, lupus-like hepatitis, mixed connective tissue disease, pemphigus, Pemphigus vulgaris, pernicious anemia, phacogenic uveitis, nodular polyarteritis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, Raynaud's syndrome Raynauds Syndrome), Reiter's Syndrome, relapsing polychondritis, Schmidt's Syndrome, sjogren, s Syndrome, sympathetic ophthalmia, high Anteremia (Takayasu, s Arteritis), temporal arteritis, thyrotoxicosis, lupus, rheumatoid arthritis, type B insulin resistance, ulcerative colitis, or Wegener's granulomatosis. 28· — kind of request item! Use of a compound of 9, 12 or 14 or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug or stereoisomer thereof for the manufacture of a medicament for the treatment of diseases of the central nervous system. 29. The use of a compound of claim 1, 9, 12 or 14 or a pharmaceutically acceptable substance thereof 127788.doc -14 - 200840567 for the use of a salt, solvate, hydrate, metabolite, prodrug or stereoisomer, It is used to manufacture medicines for the treatment of multiple sclerosis. 127788.doc 15- 200840567 七、 指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、 本案若有化學式時，請揭示最能顯示發明特徵的化學式：127788.doc 15- 200840567 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If the case has a chemical formula, please reveal the best display invention. Characteristic chemical formula: 式I 127788.docFormula I 127788.doc
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